Dihydropyrido[2,3-d]pyrimidinone compounds as cdk2 inhibitors

ABSTRACT

The present application provides dihydropyrido[2,3-d]pyrimidone inhibitors of cyclin-dependent kinase 2 (CDK2), as well as pharmaceutical compositions thereof, and methods of treating cancer using the same.

RELATED APPLICATIONS

This application claims the benefit of priority of U.S. ProvisionalApplication No. 62/744,383, filed Oct. 11, 2018, which is incorporatedherein by reference in its entirety.

TECHNICAL FIELD

This application is directed to dihydropyrido[2,3-d]pyrimidone compoundswhich inhibit cyclin-dependent kinase 2 (CDK2) and are useful fortreating cancer.

BACKGROUND

Cyclin-dependent kinases (CDKs) are a family of serine/threoninekinases. Heterodimerized with regulatory subunits known as cyclins, CDKsbecome fully activated and regulate key cellular processes includingcell cycle progression and cell division (Morgan, D. O., Annu Rev CellDev Biol, 1997. 13: 261-91). Uncontrolled proliferation is a hallmark ofcancer cells. The deregulation of the CDK activity is associated withabnormal regulation of cell-cycle, and is detected in virtually allforms of human cancers (Sherr, C. J., Science, 1996. 274(5293): 1672-7).

CDK2 is of particular interest because deregulation of CDK2 activityoccurs frequently in a variety of human cancers. CDK2 plays a crucialrole in promoting G1/S transition and S phase progression. In complexwith cyclin E (CCNE), CDK2 phosphorylates retinoblastoma pocket proteinfamily members (p 107, p 130, pRb), leading to de-repression of E2Ftranscription factors, expression of G1/S transition related genes andtransition from G1 to S phase (Henley, S. A. and F. A. Dick, Cell Div,2012, 7(1): p. 10). This in turn enables activation of CDK2/cyclin A,which phosphorylates endogenous substrates that permit DNA synthesis,replication and centrosorne duplication (Ekholm, S. V. and S. I. Reed,Curr Opin Cell Biol, 2000. 12(6): 676-84). It has been reported that theCDK2 pathway influences tumorigenesis mainly through amplificationand/or overexpression of CCNE1 and mutations that inactivate CDK2endogenous inhibitors (e.g., p 27), respectively (Xu, X., et al.,Biochemistry, 1999. 38(27): 8713-22).

CCNE1 copy-number gain and overexpression have been identified inovarian, gastric, endometrial, breast and other cancers and beenassociated with poor outcomes in these tumors (Keyomarsi, K., et al., NEngl J Med, 2002. 347(20): 1566-75; Nakayama, N., et al., Cancer, 2010.116(11): 2621-34; Au-Yeung, G., et al., Clin Cancer Res, 2017. 23(7):1862-1874; Rosen, D. G., et al., Cancer, 2006. 106(9): 1925-32).Amplification and/or overexpression of CCNE1 also reportedly contributeto trastuzumab resistance in HER2+ breast cancer and resistance toCDK4/6 inhibitors in estrogen receptor-positive breast cancer(Scaltriti, M., et al., Proc Natl Acad Sci USA, 2011. 108(9): 3761-6;Herrera-Abreu, M. T., et al., Cancer Res, 2016. 76(8): 2301-13). Variousapproaches targeting CDK2 have been shown to induce cell cycle arrestand tumor growth inhibition (Chen, Y N., et al., Proc Natl Acad Sci USA,1999. 96(8): 4325-9; Mendoza, N., et al., Cancer Res, 2003. 63(5):1020-4). Inhibition of CDK2 also reportedly restores sensitivity totrastuzumab treatment in resistant HER2+ breast tumors in a preclinicalmodel (Scaltriti, supra).

These data provide a rationale for considering CDK2 as potential targetfor new drug development in cancer associated with deregulated CDK2activity. In the last decade there has been increasing interest in thedevelopment of CDK selective inhibitors. Despite significant efforts,there are no approved agents targeting CDK2 to date (Cicenas, J., etal., Cancers (Basel), 2014. 6(4): p. 2224-42). Therefore it remains aneed to discover CDK inhibitors having novel activity profiles, inparticular those targeting CDK2. This application is directed to thisneed and others.

SUMMARY

The present invention relates to, inter alia, compounds of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein constituentmembers are defined herein.

The present invention further provides pharmaceutical compositionscomprising a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier.

The present invention further provides methods of inhibiting CDK2,comprising contacting the CDK2 with a compound of Formula (I), or apharmaceutically acceptable salt thereof.

The present invention further provides a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in any of the methodsdescribed herein.

The present invention further provides use of a compound of Formula (I),or a pharmaceutically acceptable salt thereof, for the preparation of amedicament for use in any of the methods described herein.

DETAILED DESCRIPTION Compounds

The present application provides, inter alia, a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl;

R² is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, 5-10 memberedheteroaryl-C₁₋₄ alkyl, C(═O)R^(b), C(═O)NR^(c)R^(d), C(═O)OR^(a),C(═NR^(e))R^(b), C(═NR^(e))NR^(c)R^(d), S(═O)R^(b), S(═O)NR^(c)R^(d),NR^(c)S(═O)₂R^(b), NR^(c)S(═O)₂NR^(c)R^(d), S(═O)₂R^(b), andS(═O)₂NR^(c)R^(d), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with1, 2, 3, or 4 independently selected R^(2A) substituents;

each R^(a), R^(c), and R^(d) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl,4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(2A) substituents;

each R^(b) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl, each of which are optionallysubstituted with 1, 2, 3, or 4 independently selected R^(2A)substituents;

each R^(e) is independently selected from H, CN, OH, C₁₋₄ alkyl, andC₁₋₄ alkoxy;

each R^(f) is independently selected from H, C₁₋₄ alkyl, and C₁₋₄haloalkyl;

R³ is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl, each of which is optionally substituted with 1,2, 3, or 4 independently selected R^(3A) substituents;

R⁴, R⁵, R⁶, and R⁷ have the definitions in Group (a) or (b):

Group (a):

R⁴ and R⁵ are independently selected from halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, and C₃₋₆ cycloalkyl, wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, and C₃₋₆cycloalkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(G) substituents;

or, alternatively, R⁴ and R⁵, together with the carbon atom to whichthey are attached, form a 3, 4, 5, 6, or 7 membered cycloalkyl ring or a3, 4, 5, 6, or 7 membered heterocycloalkyl ring, each of which isoptionally substituted with 1, 2, 3, or 4 independently selected R^(G)substituents;

R⁶ and R⁷ are independently selected from H, D, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, and C₃₋₆ cycloalkyl, wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, and C₃₋₆cycloalkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(G) substituents;

or, alternatively, R⁶ and R⁷, together with the carbon atom to whichthey are attached, form a 3, 4, 5, 6, or 7 membered cycloalkyl ring or a3, 4, 5, 6, or 7 membered heterocycloalkyl ring, each of which isoptionally substituted with 1, 2, 3, or 4 independently selected R^(G)substituents;

Group (b):

R⁴ and R⁵ are independently selected from H, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, and C₃₋₆ cycloalkyl, wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, and C₃₋₆cycloalkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(G) substituents;

or, alternatively, R⁴ and R⁵, together with the carbon atom to whichthey are attached, form a 3, 4, 5, 6, or 7 membered cycloalkyl ring or a3, 4, 5, 6, or 7 membered heterocycloalkyl ring, each of which isoptionally substituted with 1, 2, 3, or 4 independently selected R^(G)substituents;

R⁶ and R⁷ are independently selected from halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, and C₃₋₆ cycloalkyl, wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, and C₃₋₆cycloalkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(G) substituents;

or, alternatively, R⁶ and R⁷, together with the carbon atom to whichthey are attached, form a 3, 4, 5, 6, or 7 membered cycloalkyl ring or a3, 4, 5, 6, or 7 membered heterocycloalkyl ring, each of which isoptionally substituted with 1, 2, 3, or 4 independently selected R^(G)substituents;

each R^(2A) is independently selected from H, D, halo, CN, NO₂, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄ alkyl,OR^(a1), SR^(a1), C(═O)R^(b1), C(═O)NR^(c1)R^(d1), C(═O)OR^(a1),OC(═O)R^(b1), OC(═O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(═O)R^(b1),NR^(c1)C(═O)OR^(b1), NR^(c1)C(═O)NR^(c1)R^(d1), C(═NR^(e))R^(b1),C(═NR^(e))NR^(c1)R^(d1), NR^(c1)C(═NR^(e))NR^(c1)R^(d1), NHOR^(a1),NR^(c1)S(═O)R^(b1), NR^(c1) S(═O)NR^(c1)R^(d1), S(═O)R^(b1),S(═O)NR^(c1)R^(d1), NR^(c1)S(═O)₂R^(b1), NR^(c1)S(═O)₂NR^(c1)R^(d1),S(═O)₂R^(b1), S(═O)(═NR^(f))R^(b1), and S(═O)₂NR^(c1)R^(d1), whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄alkyl are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(2B) substituents;

each R^(a1), R^(c1), and R^(d1) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl,4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(2B) substituents;

each R^(b1) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃-10 cycloalkyl, C₆₋₁₀ aryl, 4-10membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl,each of which are optionally substituted with 1, 2, 3, or 4independently selected R^(2B) substituents;

each R^(3A) is independently selected from H, D, halo, CN, NO₂, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄ alkyl,OR^(a2), SR^(a2), C(═O)R^(b2), C(═O)NR^(c2)R^(d2), C(═O)OR^(a2),OC(═O)R^(b2), OC(═O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(═O)R^(b2),NR^(c2)C(═O)OR^(b2), NR^(c2)C(═O)NR^(c2)R^(d2), C(═NR^(e))R^(b2),C(═NR^(e))NR^(c2)R^(d2), NR^(c2)C(═NR^(e))NR^(c2)R^(d2), NHOR^(a2),NR^(c2)S(═O)R^(b2), NR^(c2)S(═O)NR^(c2)R^(d2), S(═O)R^(b2),S(═O)NR^(c2)R^(d2), NR^(c2)S(═O)₂R^(b2), NR^(c2)S(═O)₂NR^(c2)R^(d2),S(═O)₂R^(b2), S(═O)(═NR^(f))R^(b2), and S(═O)₂NR^(c2)R^(d2), whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄alkyl are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(3B) substituents;

each R^(a2), R^(c2), and R^(d2) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl,4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(3B) substituents;

each R^(b2) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, C₆-10 aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl,each of which are optionally substituted with 1, 2, 3, or 4independently selected R^(3B) substituents;

each R^(2B) and R^(3B) is independently selected from H, D, halo, CN,NO₂, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄alkyl, OR^(a23), SR^(a23), C(═O)R^(b23), C(═O)NR^(c23)R^(d23),C(═O)OR^(a23)OC(═O)R^(b23), OC(═O)NR^(c23)R^(d23), NR^(c23)R^(d23),NR^(c23)C(═O)R^(b23), NR^(c23)C(═O)OR^(b23),NR^(c23)C(═O)NR^(c23)R^(d23), C(═NR^(e))R^(b23),C(═NR^(e))NR^(c23)R^(d23), NR^(c23)C(═NR^(e))NR^(c23)R^(d23),NHOR^(a23), NR^(c23) S(═O)R^(b23), NR^(c23) S(═O)NR^(c23)R^(d23),S(═O)R^(b23), S(═O)NR^(c23)R^(d23), NR^(c23) S(═O)₂R^(b23), NR^(c23)S(═O)₂NR^(c23)R^(d23), S(═O)₂R^(b23), S(═O)(═NR^(f))R^(b23), andS(═O)₂NR^(c23)R^(d23), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with 1,2, 3, or 4 independently selected R^(G) substituents;

each R^(a23), R^(c23), and R^(d23) is independently selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl are

each optionally substituted with 1, 2, 3, or 4 independently selectedR^(G) substituents; each R^(b23) is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,each of which are optionally substituted with 1, 2, 3, or 4independently selected R^(G) substituents; and

each R^(G) is independently selected from OH, NO₂, CN, halo, C₁₋₃ alkyl,C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl, HO—C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, amino, C₁₋₃alkylamino, di(C₁₋₃ alkyl)amino, thio, C₁₋₃ alkylthio, C₁₋₃alkylsulfinyl, C₁₋₃ alkylsulfonyl, carbamyl, C₁₋₃ alkylcarbamyl, di(C₁₋₃alkyl)carbamyl, carboxy, C₁₋₃ alkylcarbonyl, C₁₋₃ alkoxycarbonyl, C₁₋₃alkylcarbonyloxy, C₁₋₃ alkylcarbonylamino, C₁₋₃ alkoxycarbonylamino,C₁₋₃ alkylaminocarbonyloxy, C₁₋₃ alkylsulfonylamino, aminosulfonyl, C₁₋₃alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₃ alkylaminocarbonylamino, and di(C₁₋₃alkyl)aminocarbonylamino.

In some embodiments:

R⁴ and R⁵ are independently selected from halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, and C₃₋₆ cycloalkyl, wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, and C₃₋₆cycloalkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(G) substituents;

or, alternatively, R⁴ and R⁵, together with the carbon atom to whichthey are attached, form a 3, 4, 5, 6, or 7 membered cycloalkyl ring or a3, 4, 5, 6, or 7 membered heterocycloalkyl ring, each of which isoptionally substituted with 1, 2, 3, or 4 independently selected R^(G)substituents;

R⁶ and R⁷ are independently selected from H, D, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, and C₃₋₆ cycloalkyl, wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, and C₃₋₆cycloalkyl are each optionally substituted with 1, 2, 3, or 4independently selected R^(G) substituents;

or, alternatively, R⁶ and R⁷, together with the carbon atom to whichthey are attached, form a 3, 4, 5, 6, or 7 membered cycloalkyl ring or a3, 4, 5, 6, or 7 membered heterocycloalkyl ring, each of which isoptionally substituted with 1, 2, 3, or 4 independently selected R^(G)substituents.

In some embodiments, R¹ is H.

In some embodiments, R² is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, each of which is optionally substitutedwith 1, 2, 3, or 4 independently selected R^(2A) substituents.

In some embodiments, R² is selected from C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl, each of which is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(2A)substituents.

In some embodiments, R² is selected from 4-7 membered heterocycloalkyland phenyl, each of which is optionally substituted with 1, 2, 3, or 4independently selected R^(2A) substituents.

In some embodiments, R² is selected from piperidin-4-yl and phenyl, eachof which is optionally substituted with 1 R^(2A) substituent.

In some embodiments, R² is selected from piperidin-4-yl and phenyl, eachof which is substituted with 1 R^(2A) substituent.

In some embodiments, each R^(2A) is independently selected from halo,CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,OR^(a1), SR^(a1), C(═O)R^(b1), C(═O)NR^(c1)R^(d1), C(═O)OR^(a1),OC(═O)R^(b1), OC(═O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(═O)R^(b1),NR^(c1)C(═O)OR^(b1), NR^(c1)C(═O)NR^(c1)R^(d1), NHOR^(a1),NR^(c1)S(═O)₂R^(b1), NR^(c1)S(═O)₂NR^(c1)R^(d1), S(═O)₂R^(b1), andS(═O)₂NR^(c1)R^(d1);

each R^(a1), R^(c1), and R^(d1) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl; and

each R^(b1) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl.

In some embodiments, each R^(2A) is independently selected fromS(═O)₂R^(b1) and S(═O)₂NR^(c1)R^(d1);

each R^(a1), R^(d1), and R^(d1) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl; and

each R^(b1) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl.

In some embodiments, each R^(2A) is independently selected fromS(═O)₂CH₃ and S(═O)₂NH₂.

In some embodiments, at least one R^(2A) is selected from S(═O)₂R^(b1)and S(═O)₂NR^(c1)R^(d1), wherein R^(b1) is C₁₋₃ alkyl; and R^(c1) andR^(d1) are each independently selected from H and C₁₋₃ alkyl.

In some embodiments, R³ is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, each of which is optionally substitutedwith 1, 2, 3, or 4 independently selected R^(3A) substituents.

In some embodiments, R³ is selected from C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl, each of which is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(3A)substituents.

In some embodiments, R³ is selected from C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,each of which is optionally substituted with 1, 2, 3, or 4 independentlyselected R^(3A) substituents.

In some embodiments, R³ is selected from C₁₋₆ haloalkyl, C₁₋₆ alkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 memberedheteroaryl-C₁₋₄ alkyl, each of which is optionally substituted with 1 or2 independently selected R^(3A) substituents.

In some embodiments, R³ is selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl, each of which is optionally substituted with 1 or 2 independentlyselected R^(3A) substituents.

In some embodiments, R³ is selected from C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, and phenyl each of which is optionally substituted with 1,2, 3, or 4 independently selected R^(3A) substituents.

In some embodiments, R³ optionally substituted with 1, 2, 3, or 4independently selected R^(3A) substituents is selected from1,1-difluorobutan-2-yl, cyclopentyl, phenyl, tetrahydrofuran-3-yl, and(1-methyl-1H-pyrazol-5-yl)methyl.

In some embodiments, R³ is selected from C₃₋₇ cycloalkyl and phenyl eachof which is optionally substituted with 1, 2, 3, or 4 independentlyselected R^(3A) substituents.

In some embodiments, R³ is selected from cyclopentyl and phenyl.

In some embodiments, each R^(3A) is independently selected from halo,CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,OR^(a2), SR^(a2), C(═O)R^(b2), C(═O)NR^(c2)R^(d2), C(═O)OR^(a2),OC(═O)R^(b2), OC(═O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(═O)R^(b2),NR^(c2)C(═O)OR^(b2), NR^(c2)C(═O)NR^(c2)R^(d2), NHOR^(a2),NR^(c2)S(═O)₂R^(b2), NR^(c2)S(═O)₂NR^(c2)R^(d2), S(═O)₂R^(b2), andS(═O)₂NR^(c2)R^(d2);

each R^(a2), R^(c2), and R^(d2) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl; and

each R^(b2) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl.

In some embodiments, each R^(3A) is independently selected from H, halo,C₁₋₆ alkyl, and C₁₋₆ haloalkyl.

In some embodiments, R⁴ and R⁵ are each independently selected from C₁₋₆alkyl and C₁₋₆ haloalkyl; or, alternatively, R⁴ and R⁵, together withthe carbon atom to which they are attached form a 3, 4, 5, or 6 memberedcycloalkyl ring.

In some embodiments, R⁴ and R⁵, together with the carbon atom to whichthey are attached form, form a cyclopropyl ring.

In some embodiments, R⁴ and R⁵ are each methyl.

In some embodiments, R⁶ and R⁷ are each independently selected from H,C₁₋₆ alkyl and C₁₋₆ haloalkyl.

In some embodiments, R⁶ and R⁷ are each H.

In some embodiments:

R¹ is H;

R² is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl, each of which is optionally substituted with 1, 2, 3, or 4independently selected R^(2A) substituents;

R³ is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl, each of which is optionally substituted with 1, 2, 3, or 4independently selected R^(3A) substituents;

R⁴ and R⁵ are each independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl;

or, alternatively, R⁴ and R⁵, together with the carbon atom to whichthey are attached form a 3, 4, 5, or 6 membered cycloalkyl ring; R⁶ andR⁷ are each independently selected from H and C₁₋₆ alkyl;

each R^(2A) is independently selected from halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a1), SR^(a1),C(═O)R^(b1), C(═O)NR^(c1)R^(d1), C(═O)OR^(a1), OC(═O)R^(b1),OC(═O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(═O)R^(b1),NR^(c1)C(═O)OR^(b1), NR^(c1)C(═O)NR^(c1)R^(d1), NHOR^(a1),NR^(c1)S(═O)₂R^(b1), NR^(c1)S(═O)₂NR^(c1)R^(d1), S(═O)₂R^(b1), andS(═O)₂NR^(c1)R^(d1);

each R^(a1), R^(c1), and R^(d1) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl;

each R^(b1) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl;

each R^(3A) is independently selected from halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a2), SR^(a2),C(═O)R^(b2), C(═O)NR^(c2)R^(d2), C(═O)OR^(a2), OC(═O)R^(b2),OC(═O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(═O)R^(b2),NR^(c2)C(═O)OR^(b2), NR^(c2)C(═O)NR^(c2)R^(d2), NHOR^(a2),NR^(c2)S(═O)₂R^(b2), NR^(c2)S(═O)₂NR^(c2)R^(d2), S(═O)₂R^(b2), andS(═O)₂NR^(c2)R^(d2);

each R^(a2), R^(c2), and R^(d2) is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl; and

each R^(b2) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl.

In some embodiments:

R¹ is H;

R² is selected from 4-7 membered heterocycloalkyl and phenyl, each ofwhich are substituted by 1 R^(2A) group;

R^(2A) is S(═O)₂R^(b1) or S(═O)₂NR^(c1)R^(d1);

R^(b1) is C₁₋₃ alkyl;

R^(c1) and R^(d1) are each independently selected from H and C₁₋₃ alkyl;

R³ is selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl, each of whichis optionally substituted with 1, 2, 3, or 4 independently selectedR^(3A) substituents;

each R^(3A) is independently selected from H, halo, C₁₋₆ alkyl, and C₁₋₆haloalkyl; R⁴ and R⁵ are each methyl;

or R⁴ and R⁵, together with the carbon atom to which they are attachedform, form a cyclopropyl ring; and

R⁶ and R⁷ are each H.

In some embodiments, 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms, attachedto carbon atoms of“alkyl”, “alkenyl”, “alkynyl”, “aryl”, “phenyl”,“cycloalkyl”, “heterocycloalkyl”, or “heteroaryl” substituents or “—C₁₋₄alkyl-” and “alkylene” linking groups, as described herein, areoptionally replaced by deuterium atoms.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the invention which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable subcombination.

At various places in the present specification, divalent linkingsubstituents are described. It is specifically intended that eachdivalent linking substituent include both the forward and backward formsof the linking substituent. For example, —NR(CR′R″)_(n)— includes both—NR(CR′R″)_(n)— and —(CR′R″)_(n)NR—. Where the structure clearlyrequires a linking group, the Markush variables listed for that groupare understood to be linking groups.

The term “n-membered” where n is an integer typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

As used herein, the phrase “optionally substituted” means unsubstitutedor substituted. The substituents are independently selected, andsubstitution may be at any chemically accessible position. As usedherein, the term “substituted” means that a hydrogen atom is removed andreplaced by a substituent. A single divalent substituent, e.g., oxo, canreplace two hydrogen atoms. It is to be understood that substitution ata given atom is limited by valency, that the designated atom's normalvalency is not exceeded, and that the substitution results in a stablecompound.

As used herein, the phrase “each ‘variable’ is independently selectedfrom” means substantially the same as wherein “at each occurrence‘variable’ is selected from.”

When any variable (e.g., R^(S)) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 1, 2, 3, or 4 R^(S),then said group may optionally be substituted with up to four R^(S)groups and R^(S) at each occurrence is selected independently from thedefinition of R^(S). Also, combinations of substituents and/or variablesare permissible only if such combinations result in stable compounds;for example the combination of a first M group and second M group in thecombination of two R groups are permissible only if such combinations ofM-M result in stable compounds (e.g., M-M is not permissible if it willform highly reactive compounds such as peroxides having O—O bonds).

Throughout the definitions, the term “C_(n-m)” indicates a range whichincludes the endpoints, wherein n and m are integers and indicate thenumber of carbons. Examples include C₁₋₃, C₁₋₄, C₁₋₆, and the like.

As used herein, the term “C_(n-m) alkyl”, employed alone or incombination with other terms, refers to a saturated hydrocarbon groupthat may be straight-chain or branched, having n to m carbons. Examplesof alkyl moieties include, but are not limited to, chemical groups suchas methyl (Me), ethyl (Et), n-propyl (n-Pr), isopropyl (iPr), n-butyl,tert-butyl, isobutyl, sec-butyl; higher homologs such as2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl,and the like. In some embodiments, the alkyl group contains from 1 to 6carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1to 2 carbon atoms.

As used herein, “C_(n-m) alkenyl” refers to an alkyl group having one ormore double carbon-carbon bonds and having n to m carbons. Examplealkenyl groups include, but are not limited to, ethenyl, n-propenyl,isopropenyl, n-butenyl, sec-butenyl, and the like. In some embodiments,the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

As used herein, “C_(n-m) alkynyl” refers to an alkyl group having one ormore triple carbon-carbon bonds and having n to m carbons. Examplealkynyl groups include, but are not limited to, ethynyl, propyn-1-yl,propyn-2-yl, and the like. In some embodiments, the alkynyl moietycontains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. As used herein, theterm “C_(n-m) alkoxy”, employed alone or in combination with otherterms, refers to a group of formula-O-alkyl, wherein the alkyl group hasn to m carbons. Example alkoxy groups include, but are not limited to,methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g.,n-butoxy and tert-butoxy), and the like. In some embodiments, the alkylgroup has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “amino” refers to a group of formula —NH₂.

As used herein, the term “aryl,” employed alone or in combination withother terms, refers to an aromatic hydrocarbon group, which may bemonocyclic or polycyclic (e.g., having 2 fused rings). The term “C_(n-m)aryl” refers to an aryl group having from n to m ring carbon atoms. Arylgroups include, e.g., phenyl, naphthyl, anthracenyl, phenanthrenyl,indanyl, indenyl, and the like. In some embodiments, the aryl group hasfrom 6 to 10 carbon atoms. In some embodiments, the aryl group is phenylor naphthyl. In some embodiments, the aryl is phenyl.

As used herein, “halo” refers to F, Cl, Br, or I. In some embodiments,halo is F, Cl, or Br. In some embodiments, halo is F or Cl. In someembodiments, halo is F. In some embodiments, halo is Cl.

As used herein, “C_(n-m) haloalkoxy” refers to a group of formula—O-haloalkyl having n to m carbon atoms. Example haloalkoxy groupsinclude OCF₃ and OCHF₂. In some embodiments, the haloalkoxy group isfluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) haloalkyl”, employed alone or incombination with other terms, refers to an alkyl group having from onehalogen atom to 2s+1 halogen atoms which may be the same or different,where “s” is the number of carbon atoms in the alkyl group, wherein thealkyl group has n to m carbon atoms. In some embodiments, the haloalkylgroup is fluorinated only. In some embodiments, the alkyl group has 1 to6, 1 to 4, or 1 to 3 carbon atoms. Example haloalkyl groups include CF₃,C₂F₅, CHF₂, CH₂F, CCl₃, CHCl₂, C₂Cl₅ and the like.

As used herein, the term “thio” refers to a group of formula —SH.

As used herein, the term “C_(n-m) alkylamino” refers to a group offormula —NH(alkyl), wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m) alkoxycarbonyl” refers to a group offormula —C(O)O-alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, the term “C_(n-m) alkylcarbonyl” refers to a group offormula —C(O)— alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, the term “C_(n-m) alkylcarbonylamino” refers to a groupof formula —NHC(O)-alkyl, wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “C_(n-m) alkoxycarbonylamino” refers to a groupof formula —NHC(O)O(C_(n-m) alkyl), wherein the alkyl group has n to mcarbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4,or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylsulfonylamino” refers to a groupof formula —NHS(O)₂-alkyl, wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “aminosulfonyl” refers to a group of formula—S(O)₂NH₂.

As used herein, the term “C_(n-m) alkylaminosulfonyl” refers to a groupof formula —S(O)₂NH(alkyl), wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “di(C_(n-m) alkyl)aminosulfonyl” refers to agroup of formula —S(O)₂N(alkyl)₂, wherein each alkyl group independentlyhas n to m carbon atoms. In some embodiments, each alkyl group has,independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “aminosulfonylamino” refers to a group offormula —NHS(O)₂NH₂.

As used herein, the term “C_(n-m) alkylaminosulfonylamino” refers to agroup of formula —NHS(O)₂NH(alkyl), wherein the alkyl group has n to mcarbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4,or 1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m) alkyl)aminosulfonylamino” refers toa group of formula —NHS(O)₂N(alkyl)₂, wherein each alkyl groupindependently has n to m carbon atoms. In some embodiments, each alkylgroup has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “aminocarbonylamino”, employed alone or incombination with other terms, refers to a group of formula —NHC(O)NH₂.

As used herein, the term “C_(n-m) alkylaminocarbonylamino” refers to agroup of formula —NHC(O)NH(alkyl), wherein the alkyl group has n to mcarbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4,or 1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m) alkyl)aminocarbonylamino” refers toa group of formula —NHC(O)N(alkyl)₂, wherein each alkyl groupindependently has n to m carbon atoms. In some embodiments, each alkylgroup has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylcarbamyl” refers to a group offormula —C(O)—NH(alkyl), wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “C_(n-m) alkylthio” refers to a group offormula —S-alkyl, wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m) alkylsulfinyl” refers to a group offormula —S(O)— alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, the term “C_(n-m) alkylsulfonyl” refers to a group offormula —S(O)₂-alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, the term “cyano-C₁₋₆ alkyl” refers to a group of formula—(C₁₋₆ alkylene)-CN. As used herein, the term “cyano-C₁₋₃ alkyl” refersto a group of formula —(C₁₋₃ alkylene)-CN.

As used herein, the term “HO—C₁₋₆ alkyl” refers to a group of formula—(C₁₋₆ alkylene)-OH. As used herein, the term “HO—C₁₋₃ alkyl” refers toa group of formula —(C₁₋₃ alkylene)-OH.

As used herein, the term “C₁₋₆ alkoxy-C₁₋₆ alkyl” refers to a group offormula —(C₁₋₆ alkylene)-O(C₁₋₆ alkyl). As used herein, the term “C₁₋₃alkoxy-C₁₋₃ alkyl” refers to a group of formula —(C₁₋₃ alkylene)-O(C₁₋₃alkyl).

As used herein, the term “carboxy” refers to a group of formula —C(O)OH.

As used herein, the term “di(C_(n-m)-alkyl)amino” refers to a group offormula —N(alkyl)₂, wherein the two alkyl groups each has,independently, n to m carbon atoms. In some embodiments, each alkylgroup independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m)-alkyl)carbamyl” refers to a groupof formula —C(O)N(alkyl)₂, wherein the two alkyl groups each has,independently, n to m carbon atoms. In some embodiments, each alkylgroup independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylcarbonyloxy” is a group offormula —OC(O)— alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, “aminocarbonyloxy” is a group of formula —OC(O)—NH₂.

As used herein, “C_(n-m) alkylaminocarbonyloxy” is a group of formula—OC(O)—NH— alkyl, wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, “di(C_(n-m) alkyl)aminocarbonyloxy” is a group offormula —OC(O)—N(alkyl)₂, wherein each alkyl group has, independently, nto m carbon atoms. In some embodiments, each alkyl group independentlyhas 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein C_(n-m) alkoxycarbonylamino refers to a group of formula—NHC(O)—O-alkyl, wherein the alkyl group has n to m carbon atoms.

As used herein, the term “carbamyl” to a group of formula —C(O)NH₂.

As used herein, the term “carbonyl”, employed alone or in combinationwith other terms, refers to a —C(O)— group.

As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbonsincluding cyclized alkyl and alkenyl groups. Cycloalkyl groups caninclude mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groups,spirocycles, and bridged rings (e.g., a bridged bicycloalkyl group).Ring-forming carbon atoms of a cycloalkyl group can be optionallysubstituted by oxo or sulfido (e.g., C(O) or C(S)). Also included in thedefinition of cycloalkyl are moieties that have one or more aromaticrings fused (i.e., having a bond in common with) to the cycloalkyl ring,for example, benzo or thienyl derivatives of cyclopentane, cyclohexane,and the like. A cycloalkyl group containing a fused aromatic ring can beattached through any ring-forming atom including a ring-forming atom ofthe fused aromatic ring. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13 or 14 ring-forming carbons (i.e., C₃₋₁₄). In someembodiments, the cycloalkyl is a C₃₋₁₂ monocyclic or bicyclic cycloalkylwhich is optionally substituted by CH₂F, CHF₂, CF₃, and CF₂CF₃. In someembodiments, the cycloalkyl is a C₃₋₁₀ monocyclic or bicycliccycloalkyl. In some embodiments, the cycloalkyl is a C₃₋₇ monocycliccycloalkyl. In some embodiments, the cycloalkyl is a C₄₋₇ monocycliccycloalkyl. In some embodiments, the cycloalkyl is a C₄₋₁₄ spirocycle orbridged cycloalkyl (e.g., a bridged bicycloalkyl group). Examplecycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl,cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, cubane, adamantane,bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptanyl,bicyclo[3.1.1]heptanyl, bicyclo[2.2.2]octanyl, spiro[3.3]heptanyl, andthe like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl.

As used herein, “heteroaryl” refers to a monocyclic or polycyclic (e.g.,having 2, 3, or 4 fused rings) aromatic heterocycle having at least oneheteroatom ring member selected from N, O, S and B. In some embodiments,the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring membersindependently selected from N, O, S and B. In some embodiments, anyring-forming N in a heteroaryl moiety can be an N-oxide. In someembodiments, the heteroaryl is a 5-10 membered monocyclic or bicyclicheteroaryl having 1, 2, 3, or 4 heteroatom ring members independentlyselected from N, O, and S. In some embodiments, the heteroaryl is a 5-10membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4heteroatom ring members independently selected from N, O, and S. In someembodiments, the heteroaryl is a 5-10 membered monocyclic or bicyclicheteroaryl having 1, 2, 3, or 4 heteroatom ring members independentlyselected from N, O, and S. In some embodiments, the heteroaryl is a 5-6monocyclic heteroaryl having 1 or 2 heteroatom ring membersindependently selected from N, O, S and B. In some embodiments, theheteroaryl is a 5-6 monocyclic heteroaryl having 1 or 2 heteroatom ringmembers independently selected from N, O, and S. In some embodiments,the heteroaryl group contains 3 to 14, 3 to 10, 4 to 14, 4 to 10, 3 to7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroarylgroup has 1 to 4 ring-forming heteroatoms, 1 to 3 ring-formingheteroatoms, 1 to 2 ring-forming heteroatoms or 1 ring-formingheteroatom. When the heteroaryl group contains more than one heteroatomring member, the heteroatoms may be the same or different. Exampleheteroaryl groups include, but are not limited to, pyridine, pyrimidine,pyrazine, pyridazine, pyrrole, pyrazole, azolyl, oxazole, isoxazole,thiazole, isothiazole, imidazole, furan, thiophene, triazole, tetrazole,thiadiazole, quinoline, isoquinoline, indole, benzothiophene,benzofuran, benzisoxazole, imidazo[1, 2-b]thiazole, purine, triazine,thieno[3,2-b]pyridine, imidazo[1,2-a]pyridine, 1,5-naphthyridine,1H-pyrazolo[4,3-b]pyridine, and the like.

A five-membered heteroaryl is a heteroaryl group having fivering-forming atoms wherein one or more (e.g., 1, 2, or 3) of thering-forming atoms are independently selected from N, O, S or B.Exemplary five-membered ring heteroaryls are thienyl, furyl, pyrrolyl,imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl,1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl,1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl, and 1,2-dihydro-1,2-azaborine.

A six-membered heteroaryl ring is a heteroaryl group having sixring-forming atoms wherein one or more (e.g., 1, 2, or 3) of thering-forming atoms are independently selected from N, O, S, and B.Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl,pyrimidinyl, triazinyl, and pyridazinyl.

As used herein, “heterocycloalkyl” refers to monocyclic or polycyclicheterocycles having at least one non-aromatic ring (saturated orpartially unsaturated ring), wherein one or more of the ring-formingcarbon atoms of the heterocycloalkyl is replaced by a heteroatomselected from N, O, S, and B, and wherein the ring-forming carbon atomsand heteroatoms of the heterocycloalkyl group can be optionallysubstituted by one or more oxo or sulfido (e.g., C(O), S(O), C(S), orS(O)₂, etc.). Heterocycloalkyl groups include monocyclic and polycyclic(e.g., having 2 fused rings) systems. Included in heterocycloalkyl aremonocyclic and polycyclic 12, 4-12, 3-10-, 4-10-, 3-7-, 4-7-, and5-6-membered heterocycloalkyl groups. Heterocycloalkyl groups can alsoinclude spirocycles and bridged rings (e.g., a 5-14 membered bridgedbiheterocycloalkyl ring having one or more of the ring-forming carbonatoms replaced by a heteroatom independently selected from N, O, S, andB). The heterocycloalkyl group can be attached through a ring-formingcarbon atom or a ring-forming heteroatom. In some embodiments, theheterocycloalkyl group contains 0 to 3 double bonds. In someembodiments, the heterocycloalkyl group contains 0 to 2 double bonds.

Also included in the definition of heterocycloalkyl are moieties thathave one or more aromatic rings fused (i.e., having a bond in commonwith) to the non-aromatic heterocyclic ring, for example, benzo orthienyl derivatives of piperidine, morpholine, azepine, etc. Aheterocycloalkyl group containing a fused aromatic ring can be attachedthrough any ring-forming atom including a ring-forming atom of the fusedaromatic ring. In some embodiments, the heterocycloalkyl group contains3 to 14 ring-forming atoms, 4 to 14 ring-forming atoms, 3 to 10ring-forming atoms, 4 to 10 ring-forming atoms, 3 to 7 ring-formingatoms, or 5 to 6 ring-forming atoms. In some embodiments, theheterocycloalkyl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to2 heteroatoms or 1 heteroatom. In some embodiments, the heterocycloalkylis a monocyclic 4-6 membered heterocycloalkyl having 1 or 2 heteroatomsindependently selected from N, O, S, and B and having one or moreoxidized ring members.

Example heterocycloalkyl groups include pyrrolidin-2-one,1,3-isoxazolidin-2-one, pyranyl, tetrahydropyran, oxetanyl, azetidinyl,morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl,tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl,isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl,imidazolidinyl, azepanyl, benzazapene, 1,2,3,4-tetrahydroisoquinoline,azabicyclo[3.1.0]hexanyl, diazabicyclo[3.1.0]hexanyl,oxabicyclo[2.1.1]hexanyl, azabicyclo[2.2.1]heptanyl,diazabicyclo[2.2.1]heptanyl, azabicyclo[3.1.1]heptanyl,diazabicyclo[3.1.1]heptanyl, azabicyclo[3.2.1]octanyl,diazabicyclo[3.2.1]octanyl, oxabicyclo[2.2.2]octanyl,azabicyclo[2.2.2]octanyl, azaadamantanyl, diazaadamantanyl,oxa-adamantanyl, azaspiro[3.3]heptanyl, diazaspiro[3.3]heptanyl,oxa-azaspiro[3.3]heptanyl, azaspiro[3.4]octanyl, diazaspiro[3.4]octanyl,oxa-azaspiro[3.4]octanyl, azaspiro[2.5]octanyl, diazaspiro[2.5]octanyl,azaspiro[4.4]nonanyl, diazaspiro[4.4]nonanyl, oxa-azaspiro[4.4]nonanyl,azaspiro[4.5]decanyl, diazaspiro[4.5]decanyl, diazaspiro[4.4]nonanyl,oxa-diazaspiro[4.4]nonanyl, and the like.

As used herein, “C_(o-p) cycloalkyl-C_(n-m) alkyl-” refers to a group offormula cycloalkyl-alkylene-, wherein the cycloalkyl has o to p carbonatoms and the alkylene linking group has n to m carbon atoms.

As used herein “C_(o-p) aryl-C_(n-m) alkyl-” refers to a group offormula aryl-alkylene-, wherein the aryl has o to p carbon atoms and thealkylene linking group has n to m carbon atoms.

As used herein, “heteroaryl-C_(n-m) alkyl-” refers to a group of formulaheteroaryl-alkylene-, wherein alkylene linking group has n to m carbonatoms.

As used herein “heterocycloalkyl-C_(n-m) alkyl-” refers to a group offormula heterocycloalkyl-alkylene-, wherein alkylene linking group has nto m carbon atoms.

As used herein, the term “alkylene” refers a divalent straight chain orbranched alkyl linking group. Examples of “alkylene groups” includemethylene, ethan-1,1-diyl, ethan-1,2-diyl, propan-1,3-dilyl,propan-1,2-diyl, propan-1,1-diyl and the like.

As used herein, the term “alkenylene” refers a divalent straight chainor branched alkenyl linking group. Examples of “alkenylene groups”include ethen-1,1-diyl, ethen-1,2-diyl, propen-1,3-diyl,2-buten-1,4-diyl, 3-penten-1,5-diyl, 3-hexen-1,6-diyl, 3-hexen-1,5-diyl,and the like.

As used herein, the term “alkynylene” refers a divalent straight chainor branched alkynyl linking group. Examples of “alkynylene groups”include propyn-1,3-diyl, 2-butyn-1,4-diyl, 3-pentyn-1,5-diyl,3-hexyn-1,6-diyl, 3-hexyn-1,5-diyl, and the like.

As used herein, the term “oxo” refers to an oxygen atom (i.e., ═O) as adivalent substituent, forming a carbonyl group when attached to a carbon(e.g., C═O or C(O)), or attached to a nitrogen or sulfur heteroatomforming a nitroso, sulfinyl or sulfonyl group.

As used herein, the term “independently selected from” means that eachoccurrence of a variable or substituent are independently selected ateach occurrence from the applicable list.

At certain places, the definitions or embodiments refer to specificrings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwiseindicated, these rings can be attached to any ring member provided thatthe valency of the atom is not exceeded. For example, an azetidine ringmay be attached at any position of the ring, whereas a pyridin-3-yl ringis attached at the 3-position.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent disclosure that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds, and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present disclosure are described and may be isolated asa mixture of isomers or as separated isomeric forms. In someembodiments, the compound has the (R)-configuration. In someembodiments, the compound has the (S)-configuration. The Formulas (e.g.,Formula (I), (II), etc.) provided herein include stereoisomers of thecompounds.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallization using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids such asβ-camphorsulfonic acid. Other resolving agents suitable for fractionalcrystallization methods include stereoisomerically pure forms ofα-methylbenzylamine (e.g., S and R forms, or diastereomerically pureforms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

Compounds provided herein also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone-enol pairs, amide-imidic acidpairs, lactam-lactim pairs, enamine-imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system, forexample, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole, 2-hydroxypyridine and 2-pyridone, and 1H— and 2H-pyrazole.Tautomeric forms can be in equilibrium or sterically locked into oneform by appropriate substitution.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.,hydrates and solvates) or can be isolated.

In some embodiments, preparation of compounds can involve the additionof acids or bases to affect, for example, catalysis of a desiredreaction or formation of salt forms such as acid addition salts.

In some embodiments, the compounds provided herein, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in the compounds providedherein. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the compounds provided herein, or saltthereof. Methods for isolating compounds and their salts are routine inthe art.

The term “compound” as used herein is meant to include allstereoisomers, geometric isomers, tautomers, and isotopes of thestructures depicted. Compounds herein identified by name or structure asone particular tautomeric form are intended to include other tautomericforms unless otherwise specified.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The present application also includes pharmaceutically acceptable saltsof the compounds described herein. The present disclosure also includespharmaceutically acceptable salts of the compounds described herein. Asused herein, “pharmaceutically acceptable salts” refers to derivativesof the disclosed compounds wherein the parent compound is modified byconverting an existing acid or base moiety to its salt form. Examples ofpharmaceutically acceptable salts include, but are not limited to,mineral or organic acid salts of basic residues such as amines; alkalior organic salts of acidic residues such as carboxylic acids; and thelike. The pharmaceutically acceptable salts of the present disclosureinclude the conventional non-toxic salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. Thepharmaceutically acceptable salts of the present disclosure can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, alcohols (e.g., methanol, ethanol,iso-propanol, or butanol) or acetonitrile (ACN) are preferred. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 17thed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal ofPharmaceutical Science, 66, 2 (1977), each of which is incorporatedherein by reference in its entirety.

Synthesis

Compounds of the invention, including salts thereof, can be preparedusing known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes, such as those inthe Schemes below.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediatesor products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups is described, e.g., in Kocienski, Protecting Groups,(Thieme, 2007); Robertson, Protecting Group Chemistry, (OxfordUniversity Press, 2000); Smith et al., March's Advanced OrganicChemistry: Reactions, Mechanisms, and Structure, 6^(th) Ed. (Wiley,2007); Peturssion et al., “Protecting Groups in Carbohydrate Chemistry,”J Chem. Educ., 1997, 74(11), 1297; and Wuts et al., Protective Groups inOrganic Synthesis, 4th Ed., (Wiley, 2006).

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), massspectrometry or by chromatographic methods such as high performanceliquid chromatography (HPLC) or thin layer chromatography (TLC).

The Schemes below provide general guidance in connection with preparingthe compounds of the invention. One skilled in the art would understandthat the preparations shown in the Schemes can be modified or optimizedusing general knowledge of organic chemistry to prepare variouscompounds of the invention.

Compounds of Formula (I) can be prepared, e.g., using a process asillustrated in the schemes below.

Compounds of Formula (I) can be prepared from an intermediate of generalformula (A). Intermediate (A) can be prepared as shown in Scheme 1.Scheme 1 shows that a diacid of formula 1-1 can be converted into asuitable diester, e.g., a methyl or ethyl ester to provide compounds offormula 1-2, which can be formylated with an appropriate reagent (e.g.,methyl or ethyl formate) to provide compounds of formula of 1-3.Reaction of compounds of formula 1-3 with an appropriate source ofguanidine, such as guanidine carbonate or guanidine hydrochloride, cangive compounds of formula 1-4. Finally, reaction of compounds of formula1-4 with a suitable chlorinating reagent e.g., phosphorus oxychloridecan give structures of general formula (A).

Intermediates of general formula A can be converted to compounds offormula (I) with various substituents at R₁ and as shown in Scheme 2.Compounds of formula (A) can be reacted with an appropriate R₂substituent using a variety of methods (e.g., reductive amination withan aldehyde or ketone, Buchwald-Hartwig amination, copper catalyzedamination, amide bond formation and others) to provide compounds offormula 2-2. The chloro group of compounds of formula 2-2 can be reactedwith an appropriate amine under Buchwald-Hartwig amination conditions toprovide compounds of Formula I.

Methods of Use

Compounds of the present disclosure can inhibit CDK2 and therefore areuseful for treating diseases wherein the underlying pathology is, whollyor partially, mediated by CDK2. Such diseases include cancer and otherdiseases with proliferation disorder. In some embodiments, the presentdisclosure provides treatment of an individual or a patient in vivousing a compound of Formula (I) or a salt or stereoisomer thereof suchthat growth of cancerous tumors is inhibited. A compound of Formula (I)or of any of the formulas as described herein, or a compound as recitedin any of the claims and described herein, or a salt or stereoisomerthereof, can be used to inhibit the growth of cancerous tumors withaberrations that activate the CDK2 kinase activity. These include, butnot limited to, cancers that are characterized by amplification oroverexpression of CCNE1 such as ovarian cancer, uterine carcinosarcomaand breast cancer and p27 inactivation such as breast cancer andmelanomas. Alternatively, a compound of Formula (I) or of any of theformulas as described herein, or a compound as recited in any of theclaims and described herein, or a salt or stereoisomer thereof, can beused in conjunction with other agents or standard cancer treatments, asdescribed below. In one embodiment, the present disclosure provides amethod for inhibiting growth of tumor cells in vitro. The methodincludes contacting the tumor cells in vitro with a compound of Formula(I) or of any of the formulas as described herein, or of a compound asrecited in any of the claims and described herein, or of a salt orstereoisomer thereof. In another embodiment, the present disclosureprovides a method for inhibiting growth of tumor cells with CCNE1amplification and overexpression in an individual or a patient. Themethod includes administering to the individual or patient in needthereof a therapeutically effective amount of a compound of Formula (I)or of any of the formulas as described herein, or of a compound asrecited in any of the claims and described herein, or a salt or astereoisomer thereof.

In some embodiments, provided herein is a method for treating cancer.The method includes administering to a patient (in need thereof), atherapeutically effective amount of a compound of Formula (I) or any ofthe formulas as described herein, a compound as recited in any of theclaims and described herein, or a salt thereof. In another embodiment,the cancer is characterized by amplification or overexpression of CCNE1.In some embodiments, the cancer is ovarian cancer or breast cancer,characterized by amplification or overexpression of CCNE1.

In some embodiments, the breast cancer is endocrine resistant breastcancer, trastuzumab resistant breast cancer, or breast cancerdemonstrating primary or acquired resistance to CDK4/6 inhibition. Insome embodiments, the breast cancer is advanced or metastatic breastcancer.

Examples of cancers that are treatable using the compounds of thepresent disclosure include, but are not limited to, bone cancer,pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous orintraocular malignant melanoma, uterine cancer, ovarian cancer, rectalcancer, cancer of the anal region, stomach cancer, testicular cancer,uterine cancer, carcinoma of the fallopian tubes, carcinoma of theendometrium, endometrial cancer, carcinoma of the cervix, carcinoma ofthe vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin'slymphoma, cancer of the esophagus, cancer of the small intestine, cancerof the endocrine system, cancer of the thyroid gland, cancer of theparathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue,cancer of the urethra, cancer of the penis, chronic or acute leukemiasincluding acute myeloid leukemia, chronic myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors ofchildhood, lymphocytic lymphoma, cancer of the bladder, cancer of thekidney or urethra, carcinoma of the renal pelvis, neoplasm of thecentral nervous system (CNS), primary CNS lymphoma, tumor angiogenesis,spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi'ssarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma,environmentally induced cancers including those induced by asbestos, andcombinations of said cancers. The compounds of the present disclosureare also useful for the treatment of metastatic cancers, especiallymetastatic cancers that express PD-Ll.

In some embodiments, cancers treatable with compounds of the presentdisclosure include melanoma (e.g., metastatic malignant melanoma), renalcancer (e.g., clear cell carcinoma), prostate cancer (e.g., hormonerefractory prostate adenocarcinoma), breast cancer, colon cancer, lungcancer (e.g., non-small cell lung cancer and small cell lung cancer),squamous cell head and neck cancer, urothelial cancer (e.g., bladder)and cancers with high microsatellite instability (MSI^(high)).Additionally, the disclosure includes refractory or recurrentmalignancies whose growth may be inhibited using the compounds of thedisclosure.

In some embodiments, cancers that are treatable using the compounds ofthe present disclosure include, but are not limited to, solid tumors(e.g., prostate cancer, colon cancer, esophageal cancer, endometrialcancer, ovarian cancer, uterine cancer, renal cancer, hepatic cancer,pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancersof the head and neck, thyroid cancer, glioblastoma, sarcoma, bladdercancer, etc.), hematological cancers (e.g., lymphoma, leukemia such asacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML),DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed orrefractory NHL and recurrent follicular), Hodgkin lymphoma or multiplemyeloma) and combinations of said cancers.

In some embodiments, cancers that are treatable using the compounds ofthe present disclosure include, but are not limited to,cholangiocarcinoma, bile duct cancer, triple negative breast cancer,rhabdomyosarcoma, small cell lung cancer, leiomyosarcoma, hepatocellularcarcinoma, Ewing's sarcoma, brain cancer, brain tumor, astrocytoma,neuroblastoma, neurofibroma, basal cell carcinoma, chondrosarcoma,epithelioid sarcoma, eye cancer, Fallopian tube cancer, gastrointestinalcancer, gastrointestinal stromal tumors, hairy cell leukemia, intestinalcancer, islet cell cancer, oral cancer, mouth cancer, throat cancer,laryngeal cancer, lip cancer, mesothelioma, neck cancer, nasal cavitycancer, ocular cancer, ocular melanoma, pelvic cancer, rectal cancer,renal cell carcinoma, salivary gland cancer, sinus cancer, spinalcancer, tongue cancer, tubular carcinoma, urethral cancer, and ureteralcancer.

In some embodiments, the compounds of the present disclosure can be usedto treat sickle cell disease and sickle cell anemia.

In some embodiments, diseases and indications that are treatable usingthe compounds of the present disclosure include, but are not limited tohematological cancers, sarcomas, lung cancers, gastrointestinal cancers,genitourinary tract cancers, liver cancers, bone cancers, nervous systemcancers, gynecological cancers, and skin cancers.

Exemplary hematological cancers include lymphomas and leukemias such asacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL),chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsedor refractory NHL and recurrent follicular), Hodgkin lymphoma,myeloproliferative diseases (e.g., primary myelofibrosis (PMF),polycythemia vera (PV), and essential thrombocytosis (ET)),myelodysplasia syndrome (MDS), T-cell acute lymphoblastic lymphoma(T-ALL) and multiple myeloma (MM).

Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma,osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma,myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, harmatoma, andteratoma.

Exemplary lung cancers include non-small cell lung cancer (NSCLC), smallcell lung cancer (SCLC), bronchogenic carcinoma, squamous cell,undifferentiated small cell, undifferentiated large cell,adenocarcinoma, alveolar (bronchiolar) carcinoma, bronchial adenoma,chondromatous hamartoma, and mesothelioma.

Exemplary gastrointestinal cancers include cancers of the esophagus(squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma),stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductaladenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors,vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors,Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma),large bowel (adenocarcinoma, tubular adenoma, villous adenoma,hamartoma, leiomyoma), and colorectal cancer.

Exemplary genitourinary tract cancers include cancers of the kidney(adenocarcinoma, Wilm's tumor [nephroblastoma]), bladder and urethra(squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma),prostate (adenocarcinoma, sarcoma), and testis (seminoma, teratoma,embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma,interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors,lipoma).

Exemplary liver cancers include hepatoma (hepatocellular carcinoma),cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellularadenoma, and hemangioma.

Exemplary bone cancers include, for example, osteogenic sarcoma(osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant celltumors Exemplary nervous system cancers include cancers of the skull(osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges(meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma,medulloblastoma, glioma, ependymoma, germinoma (pinealoma),glioblastoma, glioblastoma multiform, oligodendroglioma, schwannoma,retinoblastoma, congenital tumors), and spinal cord (neurofibroma,meningioma, glioma, sarcoma), as well as neuroblastoma andLhermitte-Duclos disease.

Exemplary gynecological cancers include cancers of the uterus(endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervicaldysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma,mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecalcell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignantteratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma,adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma,squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma),and fallopian tubes (carcinoma).

Exemplary skin cancers include melanoma, basal cell carcinoma, Merkelcell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, molesdysplastic nevi, lipoma, angioma, dermatofibroma, and keloids. In someembodiments, diseases and indications that are treatable using thecompounds of the present disclosure include, but are not limited to,sickle cell disease (e.g., sickle cell anemia), triple-negative breastcancer (TNBC), myelodysplastic syndromes, testicular cancer, bile ductcancer, esophageal cancer, and urothelial carcinoma.

It is believed that compounds of Formula (I), or any of the embodimentsthereof, may possess satisfactory pharmacological profile and promisingbiopharmaceutical properties, such as toxicological profile, metabolismand pharmacokinetic properties, solubility, and permeability. It will beunderstood that determination of appropriate biopharmaceuticalproperties is within the knowledge of a person skilled in the art, e.g.,determination of cytotoxicity in cells or inhibition of certain targetsor channels to determine potential toxicity.

The terms “individual” or “patient,” used interchangeably, refer to anyanimal, including mammals, preferably mice, rats, other rodents,rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and mostpreferably humans.

The phrase “therapeutically effective amount” refers to the amount ofactive compound or pharmaceutical agent that elicits the biological ormedicinal response in a tissue, system, animal, individual or human thatis being sought by a researcher, veterinarian, medical doctor or otherclinician.

As used herein, the term “treating” or “treatment” refers to one or moreof (1) inhibiting the disease; e.g., inhibiting a disease, condition ordisorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology);and (2) ameliorating the disease; e.g., ameliorating a disease,condition or disorder in an individual who is experiencing or displayingthe pathology or symptomatology of the disease, condition or disorder(i.e., reversing the pathology and/or symptomatology) such as decreasingthe severity of disease.

In some embodiments, the compounds of the invention are useful inpreventing or reducing the risk of developing any of the diseasesreferred to herein; e.g., preventing or reducing the risk of developinga disease, condition or disorder in an individual who may be predisposedto the disease, condition or disorder but does not yet experience ordisplay the pathology or symptomatology of the disease.

Combination Therapies I. Cancer Therapies

Cancer cell growth and survival can be impacted by dysfunction inmultiple signaling pathways. Thus, it is useful to combine differentenzyme/protein/receptor inhibitors, exhibiting different preferences inthe targets which they modulate the activities of, to treat suchconditions. Targeting more than one signaling pathway (or more than onebiological molecule involved in a given signaling pathway) may reducethe likelihood of drug-resistance arising in a cell population, and/orreduce the toxicity of treatment.

One or more additional pharmaceutical agents such as, for example,chemotherapeutics, anti-inflammatory agents, steroids,immunosuppressants, immune-oncology agents, metabolic enzyme inhibitors,chemokine receptor inhibitors, and phosphatase inhibitors, as well astargeted therapies such as Bcr-Abl, Flt-3, EGFR, HER2, JAK, c-MET,VEGFR, PDGFR, c-Kit, IGF-1R, RAF, FAK, and CDK4/6 kinase inhibitors suchas, for example, those described in WO 2006/056399 can be used incombination with the compounds of the present disclosure for treatmentof CDK2-associated diseases, disorders or conditions. Other agents suchas therapeutic antibodies can be used in combination with the compoundsof the present disclosure for treatment of CDK2-associated diseases,disorders or conditions. The one or more additional pharmaceuticalagents can be administered to a patient simultaneously or sequentially.

The compounds as disclosed herein can be used in combination with one ormore other enzyme/protein/receptor inhibitors therapies for thetreatment of diseases, such as cancer and other diseases or disordersdescribed herein. Examples of diseases and indications treatable withcombination therapies include those as described herein.

Examples of cancers include solid tumors and non-solid tumors, such asliquid tumors, blood cancers. Examples of infections include viralinfections, bacterial infections, fungus infections or parasiteinfections. For example, the compounds of the present disclosure can becombined with one or more inhibitors of the following kinases for thetreatment of cancer: Akt1, Akt2, Akt3, BCL2, CDK4/6, TGF-βR, PKA, PKG,PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR,HER2, HER3, HER4, INS-R, IDH2, IGF-1R, IR-R, PDGFαLR, PDGFβR, PI3K(alpha, beta, gamma, delta, and multiple or selective), CSF1R, KIT,FLK-II, KDR/FLK-1, FLK-4, fit-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met,PARP, Ron, Sea, TRKA, TRKB, TRKC, TAM kinases (Axl, Mer, Tyro3), FLT3,VEGFR/Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn,Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK and B-Raf. In someembodiments, the compounds of the present disclosure can be combinedwith one or more of the following inhibitors for the treatment of canceror infections. Non-limiting examples of inhibitors that can be combinedwith the compounds of the present disclosure for treatment of cancer andinfections include an FGFR inhibitor (FGFR1, FGFR2, FGFR3 or FGFR4,e.g., pemigatinib (INCY54828), INCB62079), an EGFR inhibitor (also knownas ErB-1 or HER-1; e.g., erlotinib, gefitinib, vandetanib, orsimertinib,cetuximab, necitumumab, or panitumumab), a VEGFR inhibitor or pathwayblocker (e.g., bevacizumab, pazopanib, sunitinib, sorafenib, axitinib,regorafenib, ponatinib, cabozantinib, vandetanib, ramucirumab,lenvatinib, ziv-aflibercept), a PARP inhibitor (e.g., olaparib,rucaparib, veliparib or niraparib), a JAK inhibitor (JAK1 and/or JAK2,e.g., ruxolitinib, baricitinib, itacitinib (INCB39110), an IDO inhibitor(e.g., epacadostat, NLG919, or BMS-986205, MK7162), an LSD1 inhibitor(e.g., INCB59872 and INCB60003), a TDO inhibitor, a PI3K-delta inhibitor(e.g., INCB50465 and INCB50797), a PI3K-gamma inhibitor such asPI3K-gamma selective inhibitor, a Pim inhibitor (e.g., INCB53914), aCSF1R inhibitor, a TAM receptor tyrosine kinases (Tyro-3, Axl, and Mer),an adenosine receptor antagonist (e.g., A2a/A2b receptor antagonist), anHPK1 inhibitor, a chemokine receptor inhibitor (e.g., CCR2 or CCR5inhibitor), a SHP1/2 phosphatase inhibitor, a histone deacetylaseinhibitor (HDAC) such as an HDAC8 inhibitor, an angiogenesis inhibitor,an interleukin receptor inhibitor, bromo and extra terminal familymembers inhibitors (for example, bromodomain inhibitors or BETinhibitors such as INCB54329 and INCB57643), or combinations thereof.

In some embodiments, the compound or salt described herein isadministered with a PI3Kδ inhibitor. In some embodiments, the compoundor salt described herein is administered with a JAK inhibitor. In someembodiments, the compound or salt described herein is administered witha JAK1 or JAK2 inhibitor (e.g., baricitinib or ruxolitinib). In someembodiments, the compound or salt described herein is administered witha JAK1 inhibitor. In some embodiments, the compound or salt describedherein is administered with a JAK1 inhibitor, which is selective overJAK2.

Example antibodies for use in combination therapy include, but are notlimited to, trastuzumab (e.g., anti-HER2), ranibizumab (e.g.,anti-VEGF-A), bevacizumab (AVASTIN™, e.g., anti-VEGF), panitumumab(e.g., anti-EGFR), cetuximab (e.g., anti-EGFR), rituxan (e.g.,anti-CD20), and antibodies directed to c-MET.

One or more of the following agents may be used in combination with thecompounds of the present disclosure and are presented as a non-limitinglist: a cytostatic agent, cisplatin, doxorubicin, taxotere, taxol,etoposide, irinotecan, camptosar, topotecan, paclitaxel, docetaxel,epothilones, tamoxifen, 5-fluorouracil, methotrexate, temozolomide,cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, IRESSA™(gefitinib), TARCEVA™ (erlotinib), antibodies to EGFR, intron, ara-C,adriamycin, cytoxan, gemcitabine, uracil mustard, chlormethine,ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine,triethylenethiophosphoramine, busulfan, carmustine, lomustine,streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine,6-thioguanine, fludarabine phosphate, oxaliplatin, leucovirin, ELOXATIN™(oxaliplatin), pentostatine, vinblastine, vincristine, vindesine,bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin,idarubicin, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase,teniposide 17.alpha.-ethinylestradiol, diethylstilbestrol, testosterone,Prednisone, Fluoxymesterone, Dromostanolone propionate, testolactone,megestrolacetate, methylprednisolone, methyltestosterone, prednisolone,triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide,estramustine, medroxyprogesteroneacetate, leuprolide, flutamide,toremifene, goserelin, carboplatin, hydroxyurea, amsacrine,procarbazine, mitotane, mitoxantrone, levamisole, navelbene,anastrazole, letrazole, capecitabine, reloxafine, droloxafine,hexamethylmelamine, avastin, HERCEPTIN™ (trastuzumab), BEXXAR™(tositumomab), VELCADE™ (bortezomib), ZEVALIN™ (ibritumomab tiuxetan),TRISENOX™ (arsenic trioxide), XELODA™ (capecitabine), vinorelbine,porfimer, ERBITUX™ (cetuximab), thiotepa, altretamine, melphalan,trastuzumab, lerozole, fulvestrant, exemestane, ifosfomide, rituximab,C225 (cetuximab), Campath (alemtuzumab), clofarabine, cladribine,aphidicolon, rituxan, sunitinib, dasatinib, tezacitabine, Smll,fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP, andMDL-101,731.

The compounds of the present disclosure can further be used incombination with other methods of treating cancers, for example bychemotherapy, irradiation therapy, tumor-targeted therapy, adjuvanttherapy, immunotherapy or surgery. Examples of immunotherapy includecytokine treatment (e.g., interferons, GM-CSF, G-CSF, IL-2), CRS-207immunotherapy, cancer vaccine, monoclonal antibody, bispecific ormulti-specific antibody, antibody drug conjugate, adoptive T celltransfer, Toll receptor agonists, RIG-I agonists, oncolytic virotherapyand immunomodulating small molecules, including thalidomide or JAK1/2inhibitor, PI3Kδ inhibitor and the like. The compounds can beadministered in combination with one or more anti-cancer drugs, such asa chemotherapeutic agent. Examples of chemotherapeutics include any of:abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol,altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine,bevacizumab, bexarotene, baricitinib, bleomycin, bortezomib, busulfanintravenous, busulfan oral, calusterone, capecitabine, carboplatin,carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine,cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparinsodium, dasatinib, daunorubicin, decitabine, denileukin, denileukindiftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolonepropionate, eculizumab, epirubicin, erlotinib, estramustine, etoposidephosphate, etoposide, exemestane, fentanyl citrate, filgrastim,floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib,gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelinacetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinibmesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate,lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole,lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine,methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone,nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin,paclitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim,pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine,quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib,streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide,teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan,toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard,valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, andzoledronate.

Additional examples of chemotherapeutics include proteasome inhibitors(e.g., bortezomib), thalidomide, revlimid, and DNA-damaging agents suchas melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide,carmustine, and the like.

Example steroids include corticosteroids such as dexamethasone orprednisone.

Example Bcr-Abl inhibitors include imatinib mesylate (GLEEVAC™),nilotinib, dasatinib, bosutinib, and ponatinib, and pharmaceuticallyacceptable salts. Other example suitable Bcr-Abl inhibitors include thecompounds, and pharmaceutically acceptable salts thereof, of the generaand species disclosed in U.S. Pat. No. 5,521,184, WO 04/005281, and U.S.Ser. No. 60/578,491.

Example suitable Flt-3 inhibitors include midostaurin, lestaurtinib,linifanib, sunitinib, sunitinib, maleate, sorafenib, quizartinib,crenolanib, pacritinib, tandutinib, PLX3397 and ASP2215, and theirpharmaceutically acceptable salts. Other example suitable Flt-3inhibitors include compounds, and their pharmaceutically acceptablesalts, as disclosed in WO 03/037347, WO 03/099771, and WO 04/046120.

Example suitable RAF inhibitors include dabrafenib, sorafenib, andvemurafenib, and their pharmaceutically acceptable salts. Other examplesuitable RAF inhibitors include compounds, and their pharmaceuticallyacceptable salts, as disclosed in WO 00/09495 and WO 05/028444.

Example suitable FAK inhibitors include VS-4718, VS-5095, VS-6062,VS-6063, BI853520, and GSK2256098, and their pharmaceutically acceptablesalts. Other example suitable FAK inhibitors include compounds, andtheir pharmaceutically acceptable salts, as disclosed in WO 04/080980,WO 04/056786, WO 03/024967, WO 01/064655, WO 00/053595, and WO01/014402.

Example suitable CDK4/6 inhibitors include palbociclib, ribociclib,trilaciclib, lerociclib, and abemaciclib, and their pharmaceuticallyacceptable salts. Other example suitable CDK4/6 inhibitors includecompounds, and their pharmaceutically acceptable salts, as disclosed inWO 09/085185, WO 12/129344, WO 11/101409, WO 03/062236, WO 10/075074,and WO 12/061156.

In some embodiments, the compounds of the disclosure can be used incombination with one or more other kinase inhibitors including imatinib,particularly for treating patients resistant to imatinib or other kinaseinhibitors.

In some embodiments, the compounds of the disclosure can be used incombination with a chemotherapeutic in the treatment of cancer, and mayimprove the treatment response as compared to the response to thechemotherapeutic agent alone, without exacerbation of its toxic effects.In some embodiments, the compounds of the disclosure can be used incombination with a chemotherapeutic provided herein. For example,additional pharmaceutical agents used in the treatment of multiplemyeloma, can include, without limitation, melphalan, melphalan plusprednisone [MP], doxorubicin, dexamethasone, and Velcade (bortezomib).Further additional agents used in the treatment of multiple myelomainclude Bcr-Abl, Flt-3, RAF and FAK kinase inhibitors. In someembodiments, the agent is an alkylating agent, a proteasome inhibitor, acorticosteroid, or an immunomodulatory agent. Examples of an alkylatingagent include cyclophosphamide (CY), melphalan (MEL), and bendamustine.In some embodiments, the proteasome inhibitor is carfilzomib. In someembodiments, the corticosteroid is dexamethasone (DEX). In someembodiments, the immunomodulatory agent is lenalidomide (LEN) orpomalidomide (POM). Additive or synergistic effects are desirableoutcomes of combining a CDK2 inhibitor of the present disclosure with anadditional agent.

The agents can be combined with the present compound in a single orcontinuous dosage form, or the agents can be administered simultaneouslyor sequentially as separate dosage forms.

The compounds of the present disclosure can be used in combination withone or more other inhibitors or one or more therapies for the treatmentof infections. Examples of infections include viral infections,bacterial infections, fungus infections or parasite infections.

In some embodiments, a corticosteroid such as dexamethasone isadministered to a patient in combination with the compounds of thedisclosure where the dexamethasone is administered intermittently asopposed to continuously.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be combined with another immunogenic agent, such ascancerous cells, purified tumor antigens (including recombinantproteins, peptides, and carbohydrate molecules), cells, and cellstransfected with genes encoding immune stimulating cytokines.Non-limiting examples of tumor vaccines that can be used includepeptides of melanoma antigens, such as peptides of gp 100, MAGEantigens, Trp-2, MARTI and/or tyrosinase, or tumor cells transfected toexpress the cytokine GM-CSF.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be used in combination with a vaccination protocol forthe treatment of cancer. In some embodiments, the tumor cells aretransduced to express GM-CSF. In some embodiments, tumor vaccinesinclude the proteins from viruses implicated in human cancers such asHuman Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) andKaposi's Herpes Sarcoma Virus (KHSV). In some embodiments, the compoundsof the present disclosure can be used in combination with tumor specificantigen such as heat shock proteins isolated from tumor tissue itself.In some embodiments, the compounds of Formula (I) or any of the formulasas described herein, a compound as recited in any of the claims anddescribed herein, or salts thereof can be combined with dendritic cellsimmunization to activate potent anti-tumor responses.

The compounds of the present disclosure can be used in combination withbispecific macrocyclic peptides that target Fe alpha or Fe gammareceptor-expressing effectors cells to tumor cells. The compounds of thepresent disclosure can also be combined with macrocyclic peptides thatactivate host immune responsiveness.

In some further embodiments, combinations of the compounds of thedisclosure with other therapeutic agents can be administered to apatient prior to, during, and/or after a bone marrow transplant or stemcell transplant. The compounds of the present disclosure can be used incombination with bone marrow transplant for the treatment of a varietyof tumors of hematopoietic origin.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be used in combination with vaccines, to stimulate theimmune response to pathogens, toxins, and self-antigens. Examples ofpathogens for which this therapeutic approach may be particularlyuseful, include pathogens for which there is currently no effectivevaccine, or pathogens for which conventional vaccines are less thancompletely effective. These include, but are not limited to, HIV,Hepatitis (A, B, & C), Influenza, Herpes, Giardia, Malaria, Leishmania,Staphylococcus aureus, Pseudomonas Aeruginosa.

Viruses causing infections treatable by methods of the presentdisclosure include, but are not limit to human papillomavirus,influenza, hepatitis A, B, C or D viruses, adenovirus, poxvirus, herpessimplex viruses, human cytomegalovirus, severe acute respiratorysyndrome virus, ebola virus, measles virus, herpes virus (e.g., VZV,HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus), flaviviruses,echovirus, rhinovirus, coxsackie virus, cornovirus, respiratorysyncytial virus, mumps virus, rotavirus, measles virus, rubella virus,parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus,molluscum virus, poliovirus, rabies virus, JC virus and arboviralencephalitis virus.

Pathogenic bacteria causing infections treatable by methods of thedisclosure include, but are not limited to, chlamydia, rickettsialbacteria, mycobacteria, staphylococci, streptococci, pneumococci,meningococci and conococci, klebsiella, proteus, serratia, pseudomonas,legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism,anthrax, plague, leptospirosis, and Lyme's disease bacteria.

Pathogenic fungi causing infections treatable by methods of thedisclosure include, but are not limited to, Candida (albicans, krusei,glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus(fumigatus, niger, etc.), Genus Mucorales (mucor, absidia, rhizophus),Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioidesbrasiliensis, Coccidioides immitis and Histoplasma capsulatum.

Pathogenic parasites causing infections treatable by methods of thedisclosure include, but are not limited to, Entamoeba histolytica,Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia,Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesiamicroti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani,Toxoplasma gondi, and Nippostrongylus brasiliensis.

When more than one pharmaceutical agent is administered to a patient,they can be administered simultaneously, separately, sequentially, or incombination (e.g., for more than two agents).

Methods for the safe and effective administration of most of thesechemotherapeutic agents are known to those skilled in the art. Inaddition, their administration is described in the standard literature.For example, the administration of many of the chemotherapeutic agentsis described in the “Physicians' Desk Reference” (PDR, e.g., 1996edition, Medical Economics Company, Montvale, N.J.), the disclosure ofwhich is incorporated herein by reference as if set forth in itsentirety.

II. Immune-Checkpoint Therapies

Compounds of the present disclosure can be used in combination with oneor more immune checkpoint inhibitors for the treatment of diseases, suchas cancer or infections. Exemplary immune checkpoint inhibitors includeinhibitors against immune checkpoint molecules such as CBL-B, CD20,CD28, CD40, CD122, CD96, CD73, CD47, GITR, CSF1R, JAK, PI3K delta, PI3Kgamma, TAM, arginase, HPK1, CD137 (also known as 4-1BB), ICOS, A2AR,B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, TIGIT, CD112R, VISTA, PD-1,PD-L1 and PD-L2. In some embodiments, the immune checkpoint molecule isa stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS,OX40, GITR and CD137. In some embodiments, the immune checkpointmolecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3,B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, TIGIT, and VISTA. Insome embodiments, the compounds provided herein can be used incombination with one or more agents selected from KIR inhibitors, TIGITinhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFRbeta inhibitors.

In some embodiments, the compounds provided herein can be used incombination with one or more agonists of immune checkpoint molecules,e.g., OX40, CD27, GITR, and CD137 (also known as 4-1BB).

In some embodiments, the inhibitor of an immune checkpoint molecule isanti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In someembodiments, the anti-PD-1 monoclonal antibody is nivolumab,pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001,MGA012, PDR001, AB122, or AMP-224. In some embodiments, the anti-PD-1monoclonal antibody is nivolumab or pembrolizumab. In some embodiments,the anti-PD1 antibody is pembrolizumab. In some embodiments, theanti-PD-1 monoclonal antibody is MGA012. In some embodiments, theanti-PD1 antibody is SHR-1210. Other anti-cancer agent(s) includeantibody therapeutics such as 4-1BB (e.g., urelumab, utomilumab).

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In someembodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736,MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments,the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736. In someembodiments, the inhibitor of an immune checkpoint molecule is aninhibitor of PD-1 and PD-L1, e.g., an anti-PD-1/PD-L1 bispecificantibody. In some embodiments, the anti-PD-1/PD-L1 is MCLA-136.

In some embodiments, the inhibitor is MCLA-145.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab,AGEN1884, or CP-675,206.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments,the anti-LAG3 antibody is BMS-986016, LAG525, or INCAGN2385.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TIM3, e.g., an anti-TIM3 antibody. In some embodiments,the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments,the anti-GITR antibody is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228,BMS-986156, GWN323, or MEDI1873.

In some embodiments, the inhibitor of an immune checkpoint molecule isan agonist of OX40, e.g., OX40 agonist antibody or OX40L fusion protein.In some embodiments, the anti-OX40 antibody is MEDI0562, MOXR-0916,PF-04518600, GSK3174998, or BMS-986178. In some embodiments, the OX40Lfusion protein is MEDI6383.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD20, e.g., an anti-CD20 antibody. In some embodiments,the anti-CD20 antibody is obinutuzumab or rituximab.

The compounds of the present disclosure can be used in combination withbispecific antibodies. In some embodiments, one of the domains of thebispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3,CD137, ICOS, CD3 or TGFβ receptor.

In some embodiments, the compounds of the disclosure can be used incombination with one or more metabolic enzyme inhibitors. In someembodiments, the metabolic enzyme inhibitor is an inhibitor of IDO1,TDO, or arginase. Examples of IDO1 inhibitors include epacadostat,NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099 and LY338196.

As provided throughout, the additional compounds, inhibitors, agents,etc. can be combined with the present compound in a single or continuousdosage form, or they can be administered simultaneously or sequentiallyas separate dosage forms.

Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, the compounds of the disclosure can beadministered in the form of pharmaceutical compositions. Thesecompositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is desired and uponthe area to be treated. Administration may be topical (includingtransdermal, epidermal, ophthalmic and to mucous membranes includingintranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalationor insufflation of powders or aerosols, including by nebulizer;intratracheal or intranasal), oral, or parenteral. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be, forexample, by a continuous perfusion pump. Pharmaceutical compositions andformulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable.

This disclosure also includes pharmaceutical compositions which contain,as the active ingredient, the compound of the disclosure or apharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers (excipients). In someembodiments, the composition is suitable for topical administration.

In making the compositions of the disclosure, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, for example, a capsule, sachet,paper, or other container. When the excipient serves as a diluent, itcan be a solid, semi-solid, or liquid material, which acts as a vehicle,carrier or medium for the active ingredient. Thus, the compositions canbe in the form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, for example, up to 10% byweight of the active compound, soft and hard gelatin capsules,suppositories, sterile injectable solutions, and sterile packagedpowders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g., about 40 mesh.

The compounds of the disclosure may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the disclosure can beprepared by processes known in the art, e.g., see International App. No.WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the disclosure can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1000 mg (1 g), more usually about 100to about 500 mg, of the active ingredient. The term “unit dosage forms”refers to physically discrete units suitable as unitary dosages forhuman subjects and other mammals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect, in association with a suitable pharmaceuticalexcipient.

In some embodiments, the compositions of the disclosure contain fromabout 5 to about 50 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 5 to about 10, about 10 to about 15, about 15 to about20, about 20 to about 25, about 25 to about 30, about 30 to about 35,about 35 to about 40, about 40 to about 45, or about 45 to about 50 mgof the active ingredient.

In some embodiments, the compositions of the disclosure contain fromabout 50 to about 500 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 50 to about 100, about 100 to about 150, about 150 toabout 200, about 200 to about 250, about 250 to about 300, about 350 toabout 400, or about 450 to about 500 mg of the active ingredient.

In some embodiments, the compositions of the disclosure contain fromabout 500 to about 1000 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 500 to about 550, about 550 to about 600, about 600 toabout 650, about 650 to about 700, about 700 to about 750, about 750 toabout 800, about 800 to about 850, about 850 to about 900, about 900 toabout 950, or about 950 to about 1000 mg of the active ingredient.

Similar dosages may be used of the compounds described herein in themethods and uses of the disclosure.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present disclosure. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, about 0.1 to about 1000 mg of the activeingredient of the present disclosure.

The tablets or pills of the present disclosure can be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action. For example, the tablet or pill can comprise an innerdosage and an outer dosage component, the latter being in the form of anenvelope over the former. The two components can be separated by anenteric layer which serves to resist disintegration in the stomach andpermit the inner component to pass intact into the duodenum or to bedelayed in release.

A variety of materials can be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol, andcellulose acetate.

The liquid forms in which the compounds and compositions of the presentdisclosure can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions can be nebulized by use of inert gases. Nebulized solutionsmay be breathed directly from the nebulizing device or the nebulizingdevice can be attached to a face mask, tent, or intermittent positivepressure breathing machine. Solution, suspension, or powder compositionscan be administered orally or nasally from devices which deliver theformulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, for example, liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.,glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, for example,glycerol, hydroxyethyl cellulose, and the like. In some embodiments,topical formulations contain at least about 0.1, at least about 0.25, atleast about 0.5, at least about 1, at least about 2, or at least about 5wt % of the compound of the disclosure. The topical formulations can besuitably packaged in tubes of, for example, 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present disclosure can varyaccording to, for example, the particular use for which the treatment ismade, the manner of administration of the compound, the health andcondition of the patient, and the judgment of the prescribing physician.The proportion or concentration of a compound of the disclosure in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of thedisclosure can be provided in an aqueous physiological buffer solutioncontaining about 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

The compositions of the disclosure can further include one or moreadditional pharmaceutical agents such as a chemotherapeutic, steroid,anti-inflammatory compound, or immunosuppressant, examples of which arelisted herein.

Labeled Compounds and Assay Methods Another aspect of the presentdisclosure relates to labeled compounds of the disclosure(radio-labeled, fluorescent-labeled, etc.) that would be useful not onlyin imaging techniques but also in assays, both in vitro and in vivo, forlocalizing and quantitating CDK2 in tissue samples, including human, andfor identifying CDK2 activators by inhibition binding of a labeledcompound. Substitution of one or more of the atoms of the compounds ofthe present disclosure can also be useful in generating differentiatedADME (Adsorption, Distribution, Metabolism and Excretion.) Accordingly,the present disclosure includes CDK2 assays that contain such labeled orsubstituted compounds.

The present disclosure further includes isotopically-labeled compoundsof the disclosure. An “isotopically” or “radio-labeled” compound is acompound of the disclosure where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present disclosure include but are not limited to ²H(also written as D for deuterium), ³H (also written as T for tritium),¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br,⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. For example, one or more hydrogenatoms in a compound of the present disclosure can be replaced bydeuterium atoms (e.g., one or more hydrogen atoms of a C₁₋₆ alkyl groupof Formula (I) can be optionally substituted with deuterium atoms, suchas —CD₃ being substituted for —CH₃). In some embodiments, alkyl groupsof the disclosed Formulas (e.g., Formula (I)) can be perdeuterated.

One or more constituent atoms of the compounds presented herein can bereplaced or substituted with isotopes of the atoms in natural ornon-natural abundance. In some embodiments, the compound includes atleast one deuterium atom. For example, one or more hydrogen atoms in acompound presented herein can be replaced or substituted by deuterium(e.g., one or more hydrogen atoms of a C₁₋₆ alkyl group can be replacedby deuterium atoms, such as —CD₃ being substituted for —CH₃). In someembodiments, the compound includes two or more deuterium atoms. In someembodiments, the compound includes 1-2, 1-3, 1-4, 1-5, or 1-6 deuteriumatoms. In some embodiments, all of the hydrogen atoms in a compound canbe replaced or substituted by deuterium atoms.

In some embodiments, 1, 2, 3, 4, 5, 6, 7, or 8 hydrogen atoms, attachedto carbon atoms of alkyl, alkenyl, alkynyl, aryl, phenyl, cycloalkyl,heterocycloalkyl, or heteroaryl substituents or —C₁₋₄ alkyl-, alkylene,alkenylene and alkynylene linking groups, as described herein, areoptionally replaced by deuterium atoms.

Synthetic methods for including isotopes into organic compounds areknown in the art (Deuterium Labeling in Organic Chemistry by Alan F.Thomas (New York, N.Y., Appleton-Century-Crofts, 1971; The Renaissanceof H/D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and JochenZimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistryof Isotopic Labelling by James R. Hanson, Royal Society of Chemistry,2011). Isotopically labeled compounds can be used in various studiessuch as NMR spectroscopy, metabolism experiments, and/or assays.

Substitution with heavier isotopes, such as deuterium, may affordcertain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances. (seee.g., A. Kerekes et al. J. Med. Chem. 2011, 54, 201-210; R. Xu et al. J.Label Compd. Radiopharm. 2015, 58, 308-312). In particular, substitutionat one or more metabolism sites may afford one or more of thetherapeutic advantages.

The radionuclide that is incorporated in the instant radio-labeledcompounds will depend on the specific application of that radio-labeledcompound. For example, for in vitro CDK2 labeling and competitionassays, compounds that incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹I, or ³⁵S canbe useful. For radio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I,¹³¹I, ⁷⁵Br, ⁷⁶Br, or ⁷⁷Br can be useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments, the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S, and ⁸²Br.

The present disclosure can further include synthetic methods forincorporating radio-isotopes into compounds of the disclosure. Syntheticmethods for incorporating radio-isotopes into organic compounds are wellknown in the art, and an ordinary skill in the art will readilyrecognize the methods applicable for the compounds of disclosure.

A labeled compound of the disclosure can be used in a screening assay toidentify/evaluate compounds. For example, a newly synthesized oridentified compound (i.e., test compound) which is labeled can beevaluated for its ability to bind activate CDK2 by monitoring itsconcentration variation when contacting with CDK2, through tracking ofthe labeling. For example, a test compound (labeled) can be evaluatedfor its ability to reduce binding of another compound which is known toinhibit CDK2 (i.e., standard compound). Accordingly, the ability of atest compound to compete with the standard compound for binding to CDK2directly correlates to its binding affinity. Conversely, in some otherscreening assays, the standard compound is labeled and test compoundsare unlabeled. Accordingly, the concentration of the labeled standardcompound is monitored in order to evaluate the competition between thestandard compound and the test compound, and the relative bindingaffinity of the test compound is thus ascertained.

Kits

The present disclosure also includes pharmaceutical kits useful, forexample, in the treatment or prevention of CDK2-associated diseases ordisorders (such as, e.g., cancer, an inflammatory disease, acardiovascular disease, or a neurodegenerative disease) which includeone or more containers containing a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of thedisclosure. Such kits can further include, if desired, one or more ofvarious conventional pharmaceutical kit components, such as, forexample, containers with one or more pharmaceutically acceptablecarriers, additional containers, etc., as will be readily apparent tothose skilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results.

EXAMPLES

Experimental procedures for compounds of the invention are providedbelow. Preparatory LC-MS purifications of some of the compounds preparedwere performed on Waters mass directed fractionation systems. The basicequipment setup, protocols, and control software for the operation ofthese systems have been described in detail in the literature. See e.g.,“Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K.Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MSConfigurations and Methods for Parallel Synthesis Purification”, K.Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi.Chem., 5, 670 (2003); and “Preparative LC-MS Purification: ImprovedCompound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A.Combs, J. Combi. Chem., 6, 874-883 (2004). The separated compounds weretypically subjected to analytical liquid chromatography massspectrometry (LCMS) for purity check under the following conditions:Instrument; Agilent 1100 series, LC/MSD, Column: Waters Sunfire™ C₁₈ 5μm particle size, 2.1×5.0 mm, Buffers: mobile phase A: 0.025% TFA inwater and mobile phase B: acetonitrile; gradient 2% to 80% of B in 3minutes with flow rate 2.0 mL/minute.

Some of the compounds prepared were also separated on a preparativescale by reverse-phase high performance liquid chromatography (RP-HPLC)with MS detector or flash chromatography (silica gel) as indicated inthe Examples. Typical preparative reverse-phase high performance liquidchromatography (RP-HPLC) column conditions are as follows:

pH=2 purifications: Waters Sunfire™ C₁₈ 5 μm particle size, 19×100 mmcolumn, eluting with mobile phase A: 0.1% TFA (trifluoroacetic acid) inwater and mobile phase B: acetonitrile; the flow rate was 30 mL/minute,the separating gradient was optimized for each compound using theCompound Specific Method Optimization protocol as described in theliterature (see “Preparative LCMS Purification: Improved CompoundSpecific Method Optimization”, K. Blom, B. Glass, R. Sparks, A. Combs,J. Comb. Chem., 6, 874-883 (2004)). Typically, the flow rate used withthe 30×100 mm column was 60 mL/minute.

pH=10 purifications: Waters XBridge C₁₈ 5 μm particle size, 19×100 mmcolumn, eluting with mobile phase A: 0.15% NH₄OH in water and mobilephase B: acetonitrile; the flow rate was 30 mL/minute, the separatinggradient was optimized for each compound using the Compound SpecificMethod Optimization protocol as described in the literature (See“Preparative LCMS Purification: Improved Compound Specific MethodOptimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem.,6, 874-883 (2004)). Typically, the flow rate used with 30×100 mm columnwas 60 mL/minute.

Example 1.4-((8-cyclopentyl-6,6-dimethyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)amino)benzenesulfonamide

Step 1. 5-bromo-N-cyclopentyl-2-methoxypyrimidin-4-amine

To a solution of 5-bromo-2,4-dichloropyrimidine (3.08 ml, 24.05 mmol) inTHF (80 mL) was added cyclopentanamine (2.62 mL, 26.5 mmol) and thereaction mixture stirred at r.t. for 2 hr, then filtered. The filtratewas concentrated and dissolved in sodium methoxide in MeOH (21% w/w, 3mL), then heated to reflux for 2 hr. The mixture was diluted with waterand ethyl acetate and the layers were separated. The organic layer waswashed with water and brine, dried over sodium sulfate and concentrated.The residue was purified by Biotage Isolera™ (0-50% ethyl acetate inhexanes) to provide the desired product as a white solid (4.7 g, 72%).LCMS calculated for C₁₀H₁₅BrN₃O (M+H)⁺: m/z=272.0/274.0; Found:272.0/274.0.

Step 2. ethyl 3-(4-(cyclopentylamino)-2-methoxypyrimidin-5-yl)propanoate

To a mixture of 5-bromo-N-cyclopentyl-2-methoxypyrimidin-4-amine (500mg, 1.837 mmol), triethylamine (512 μL, 3.67 mmol), ethyl acrylate (300μL, 2.76 mmol) and tetrakis(triphenylphosphine)palladium(0) (212 mg,0.184 mmol) was added DMF (6 mL) and the reaction flask was evacuated,back filled with nitrogen, then stirred at 120° C. overnight. Themixture was then poured into ethyl acetate/water and the layersseparated. The aqueous layer was extracted with ethyl acetate and thecombined organics were washed with water and brine, dried over sodiumsulfate and concentrated. The crude product was purified by BiotageIsolera™ (0-100% ethyl acetate in hexanes). The intermediate wasdissolved in EtOH (6 mL) and palladium on carbon (10%, 391 mg, 0.367mmol) was added. The reaction flask was evacuated, then backfilled withhydrogen gas from a balloon. The reaction mixture was stirred at r.t.for 3 hr, then diluted with ethyl acetate and filtered through a plug ofCelite. The filtrate was concentrated and the crude product used in thenext step without further purification (340 mg, 63%). LCMS calculatedfor C₁₅H₂₄N₃O₃ (M+H)⁺: m/z=294.2; Found: 294.2.

Step 3.8-cyclopentyl-2-methoxy-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one

To a solution of ethyl3-(4-(cyclopentylamino)-2-methoxypyrimidin-5-yl)propanoate (5.0 g, 17.04mmol) in THF (28 mL)/Water (28 mL) was added lithium hydroxide hydrate(1.073 g, 25.6 mmol) and the reaction mixture was stirred at r.t. for 30mins, then quenched with HCl (12 N, 2.13 mL, 25.6 mmol) andconcentrated. The crude product was dissolved in DMF (4 mL) and HATU(7.13 g, 18.75 mmol) and Hunig's base (5.95 mL, 34.1 mmol) was added.The reaction was then stirred at r.t. for 2 hr, quenched with water andextracted with ethyl acetate. The organic layer was washed with waterand brine, dried over sodium sulfate and concentrated. The crude productwas purified by Biotage Isolera™ (20-100% ethyl acetate in hexanes) toprovide the desired product (2.01 g, 48%). LCMS calculated forC₁₃H₁₈N₃O₂ (M+H)⁺: m/z=248.2; Found: 248.2.

Step 4.8-cyclopentyl-2-methoxy-6,6-dimethyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one

To a solution of8-cyclopentyl-2-methoxy-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (501mg, 2.026 mmol) in DMF (10 mL) were added methyl iodide (380 μL, 6.08mmol) and sodium hydride (60% in mineral oil, 284 mg, 7.09 mmol) and thereaction mixture was heated to 65° C. for 2 hr. The mixture was quenchedwith water and extracted with ethyl acetate. The organic layer waswashed with water and brine, dried over sodium sulfate and concentrated.The crude residue was purified by Biotage Isolera™ (0-100% ethyl acetatein hexanes) to provide the desired product as a colorless oil (303 mg,54%). LCMS calculated for C₁₅H₂N₃O₂ (M+H)⁺: m/z=276.2; Found: 276.2.

Step 5.8-cyclopentyl-6,6-dimethyl-7-oxo-2,3,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-2-yltrifluoromethanesulfonate

To a solution of8-cyclopentyl-2-methoxy-6,6-dimethyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one(131 mg, 0.476 mmol) in acetonitrile (2.4 mL) were added sodium iodide(143 mg, 0.952 mmol) and TMS-C1 (122 μL, 0.952 mmol) and the reactionmixture was stirred at r.t. overnight, then quenched with water andextracted with ethyl acetate. The organic layer was washed withsaturated aq. sodium thiosulfate, water and brine, dried over sodiumsulfate and concentrated. The crude product was dissolved in DCM (2.5mL) and pyridine (42.3 μl, 0.523 mmol) was added. The reaction mixturewas cooled to 0° C. and trifluoromethanesulfonic anhydride (96 μL, 0.571mmol) was added dropwise. The reaction mixture was then warmed to r.t.and stirred for 2 hr, then quenched with sat. sodium bicarbonate andextracted with DCM. The organic layer was dried over sodium sulfate andconcentrated. The crude product was used in the next step withoutfurther purification (141 mg, 75%). LCMS calculated for C₁₅H₂₁F₃N₃O₄S(M+H)⁺: m/z=396.2; Found: 396.2.

Step 6.4-((8-cyclopentyl-6,6-dimethyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)amino)benzenesulfonamide

To a mixture of8-cyclopentyl-6,6-dimethyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yltrifluoromethanesulfonate (20 mg, 0.051 mmol), 4-aminobenzenesulfonamide(17.51 mg, 0.102 mmol), XantPhos Pd G2 (4.52 mg, 5.08 μmol) andpotassium carbonate (70.3 mg, 0.508 mmol) was added 1,4-Dioxane (508 μL)and the reaction flask was evacuated, back filled with nitrogen, thenstirred at 100° C. for 2 hr. The mixture was then diluted with MeOH andpurified with prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMScalculated for C₂₀H₂₆N₅O₃S (M+H)⁺: m/z=416.2; Found: 416.2.

Example 2.8-cyclopentyl-6,6-dimethyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one

This compound was prepared in an analogous fashion to Example 1, Step 6using 1-(methylsulfonyl)piperidin-4-amine in place of4-aminobenzenesulfonamide and RuPhos Pd G2 in place of XantPhos Pd G2.LCMS calculated for C₂₀H₃₂N₅O₃S (M+H)⁺: m/z=422.2; Found: 422.2. ¹H NMR(600 MHz, DMSO) δ 8.01 (s, 1H), 5.44-5.22 (m, 1H), 3.85 (bs, 1H), 3.59(d, J=12.3 Hz, 1H), 2.9 (s, 3H), 2.85 (t, J=12.2, 2.6 Hz, 1H), 2.60 (s,2H), 2.05 (s, 1H), 1.98 (d, J=16.3 Hz, 1H), 1.93-1.87 (m, 1H), 1.74 (s,1H), 1.59 (m, 2H), 1.09 (s, 6H).

Example 3.6,6-dimethyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)-8-phenyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one

Step 1. dimethyl 2,2-dimethylpentanedioate

To a solution of 3,3-dimethyldihydro-2H-pyran-2,6(3H)-dione (10 g, 70.3mmol) in methanol (100 ml) was added 10 drops of concentrated sulfuricacid and the reaction mixture heated to 60° C. overnight. The mixturewas then concentrated. The residue was diluted with ethyl acetate andwashed with sat. sodium bicarbonate and brine, then dried over sodiumsulfate and concentrated. The crude product was used in the next stepwithout further purification.

Step 2. methyl3-(2-amino-6-oxo-1,6-dihydropyrimidin-5-yl)-2,2-dimethylpropanoate

To a solution of diisopropylamine (5.32 mL, 37.4 mmol) in THF (12 mL) at−78° C. was added n-BuLi (2.5M in hexanes, 14.94 mL, 37.4 mmol) dropwiseand the reaction mixture stirred at −78° C. for 1 hr. A solution ofdimethyl 2,2-dimethylpentanedioate (5.86 g, 31.1 mmol) in THF (20 mL)was then added dropwise and the reaction mixture stirred an additional1.5 hr at −78° C. Methyl formate (2.88 mL, 46.7 mmol) was then added andthe reaction mixture stirred at −78° C. for 1 hr, then quenched withsat. ammonium chloride. After warming to r.t., the mixture was dilutedwith ethyl acetate/water and the layers separated. The organic layer waswashed with water and brine, dried over sodium sulfate and concentrated.The residue was dissolved in MeOH (10 mL) and guanidine carbonate (5.61g, 31.1 mmol) was added. The reaction mixture was heated to 60° C.overnight, then concentrated and purified by Biotage Isolera™ (2-12%methanol in dichloromethane) to provide the desired product as a whitesolid (2.45 g, 35%). LCMS calculated for C₁₀H₁₆N₃O₃ (M+H)⁺: m/z=226.2;Found: 226.2.

Step 3. methyl3-(4-chloro-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-5-yl)-2,2-dimethylpropanoate

Methyl3-(2-amino-6-oxo-1,6-dihydropyrimidin-5-yl)-2,2-dimethylpropanoate (2.45g, 10.88 mmol) was dissolved in POCl₃ (10 mL) and heated to 100° C.overnight, then slowly added to sat. sodium bicarbonate. The mixture wasextracted with DCM and the organic layer washed with sat. sodiumbicarbonate and brine, dried over sodium sulfate and concentrated. Tothe intermediate were added DMF (36.3 mL),1-(methylsulfonyl)piperidin-4-one (2.506 g, 14.14 mmol), TFA (5.03 ml,65.3 mmol) and sodium triacetoxyborohydride (5.76 g, 27.2 mmol) and thereaction mixture was stirred at r.t. for 5 hr, then quenched with sat.sodium bicarbonate and extracted with DCM. The organic layer was washedwith water and brine, dried over sodium sulfate and concentrated. Theresidue was purified by Biotage Isolera™ (2-12% methanol in DCM) toprovide the desired product as a yellow solid (2.2 g, 50%). LCMScalculated for C₁₆H₂₆ClN₄O₄S (M+H)⁺: m/z=404.2/406.2; Found:404.2/406.2.

Step 4.6,6-dimethyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)-8-phenyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one

To a mixture of methyl3-(4-chloro-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-5-yl)-2,2-dimethylpropanoate(21 mg, 0.052 mmol), aniline (9.47 L, 0.104 mmol), Ruphos Pd G2 (4.03mg, 5.19 μmol) and cesium carbonate (50.7 mg, 0.156 mmol) was added1,4-dioxane (519 μL) and the reaction flask was evacuated, back filledwith nitrogen, then stirred at 100° C. overnight. The reaction mixturewas diluted with MeOH and purified with prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). LCMS calculated for C₂₁H₂₈N₅O₃S (M+H)⁺:m/z=430.2; Found: 430.2.

Example 4.8-(1,1-difluorobutan-2-yl)-6,6-dimethyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one

This compound was prepared in an analogous fashion to Example 3, step 4using 1,1-difluorobutan-2-amine as the coupling partner. The product wasisolated as a racemic mixture. LCMS calculated for C₁₉H₃₀F₂N₅O₃S (M+H)⁺:m/z=446.2; Found: 446.2.

Example 5.6,6-dimethyl-8-((1-methyl-1H-pyrazol-5-yl)methyl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one

This compound was prepared in an analogous fashion to Example 3, step 4using (1-methyl-1H-pyrazol-5-yl)methanamine as the coupling partner.LCMS calculated for C₂₀H₃₀N₇O₃S (M+H)⁺: m/z=448.2; Found: 448.2.

Example 6.6,6-dimethyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)-8-(tetrahydrofuran-3-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one

This compound was prepared in an analogous fashion to Example 3, step 4tetrahydrofuran-3-amine as the coupling partner. The product wasobtained in racemic form. LCMS calculated for C₁₉H₃₀N₅O₄S (M+H)⁺:m/z=424.2; Found: 424.2.

Example A. CDK2/Cyclin E1 HTRF Enzyme Activity Assay

CDK2/Cyclin E1 enzyme activity assays utilize full-length human CDK2co-expressed as N-terminal GST-tagged protein with FLAG-Cyclin E1 in abaculovirus expression system (Carna Product Number 04-165). Assays areconducted in white 384-well polystyrene plates in a final reactionvolume of 8 μL. CDK2/Cyclin E1 (0.25 nM) is incubated with compounds (40nL serially diluted in DMSO) in the presence of ATP (50 μM or 1 mM) and50 nM ULight™-labeled eIF4E-binding protein 1 (THR37/46) peptide(PerkinElmer) in assay buffer (containing 50 mM HEPES pH 7.5, 1 mM EGTA,10 mM MgCl₂, 2 mM DTT, 0.05 mg/ml BSA, and 0.01% Tween 20) for 60minutes at room temperature. The reactions are stopped by the additionof EDTA and Europium-labeled anti-phospho-4E-BP 1 antibody(PerkinElmer), for a final concentration of 15 mM and 1.5 nM,respectively. HTRF signals are read after 1 hour at room temperature ona PHERAstar FS plate reader (BMG Labtech). Data is analyzed with IDBSXLFit and GraphPad Prism 5.0 software using a three or four parameterdose response curve to determine IC₅₀ for each compound. The IC₅₀ dataas measured for the Examples at 1 mM ATP in the assay of Example A isshown in Table 1.

TABLE 1 Example IC₅₀ (nM) 1 + 2 + 3 +++ 4 ++ 5 +++ 6 +++ + refers to ≤10nM ++ refers to >10 nM to 100 nM +++ refers to >100 nM to 500 nM ++++refers to >500 nM to 1000 nM

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

What is claimed is:
 1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is selectedfrom H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl; R² is selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄ alkyl,C(═O)R^(b), C(═O)NR^(c)R^(d), C(═O)OR^(a), C(═NR^(e))R^(b),C(═NR^(e))NR^(c)R^(d), S(═O)R^(b), S(═O)NR^(c)R^(d), NR^(c)S(═O)₂R^(b),NR^(c)S(═O)₂NR^(c)R^(d), S(═O)₂R^(b), and S(═O)₂NR^(c)R^(d), whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄alkyl are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(2A) substituents; each R^(a), R^(c), and R^(d) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl,4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(2A) substituents; each R^(b) is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl,each of which are optionally substituted with 1, 2, 3, or 4independently selected R^(2A) substituents; each R^(e) is independentlyselected from H, CN, OH, C₁₋₄ alkyl, and C₁₋₄ alkoxy; each R^(f) isindependently selected from H, C₁₋₄ alkyl, and C₁₋₄ haloalkyl; R³ isselected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl,4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl, each of which is optionally substituted with 1,2, 3, or 4 independently selected R^(3A) substituents; R⁴, R⁵, R⁶, andR⁷ have the definitions in Group (a) or (b): Group (a): R⁴ and R⁵ areindependently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, and C₃₋₆ cycloalkyl, wherein said C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, and C₃₋₆ cycloalkyl are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(G)substituents; or, alternatively, R⁴ and R⁵, together with the carbonatom to which they are attached, form a 3, 4, 5, 6, or 7 memberedcycloalkyl ring or a 3, 4, 5, 6, or 7 membered heterocycloalkyl ring,each of which is optionally substituted with 1, 2, 3, or 4 independentlyselected R^(G) substituents; R⁶ and R⁷ are independently selected fromH, D, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, andC₃₋₆ cycloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, and C₃₋₆ cycloalkyl are each optionally substituted with1, 2, 3, or 4 independently selected R^(G) substituents; or,alternatively, R⁶ and R⁷, together with the carbon atom to which theyare attached, form a 3, 4, 5, 6, or 7 membered cycloalkyl ring or a 3,4, 5, 6, or 7 membered heterocycloalkyl ring, each of which isoptionally substituted with 1, 2, 3, or 4 independently selected R^(G)substituents; Group (b): R⁴ and R⁵ are independently selected from H,halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, and C₃₋₆cycloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, and C₃₋₆ cycloalkyl are each optionally substituted with 1,2, 3, or 4 independently selected R^(G) substituents; or, alternatively,R⁴ and R⁵, together with the carbon atom to which they are attached,form a 3, 4, 5, 6, or 7 membered cycloalkyl ring or a 3, 4, 5, 6, or 7membered heterocycloalkyl ring, each of which is optionally substitutedwith 1, 2, 3, or 4 independently selected R^(G) substituents; R⁶ and R⁷are independently selected from halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, and C₃₋₆ cycloalkyl, wherein said C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, and C₃₋₆ cycloalkyl are eachoptionally substituted with 1, 2, 3, or 4 independently selected R^(G)substituents; or, alternatively, R⁶ and R⁷, together with the carbonatom to which they are attached, form a 3, 4, 5, 6, or 7 memberedcycloalkyl ring or a 3, 4, 5, 6, or 7 membered heterocycloalkyl ring,each of which is optionally substituted with 1, 2, 3, or 4 independentlyselected R^(G) substituents; each R^(2A) is independently selected fromH, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, 5-10 memberedheteroaryl-C₁₋₄ alkyl, OR^(a1), SR^(a1), C(═O)R^(b1),C(═O)NR^(c1)R^(d1), C(═O)OR^(a1), OC(═O)R^(b1), OC(═O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(═O)R^(b1), NR^(c1)C(═O)OR^(b1),NR^(c1)C(═O)NR^(c1)R^(d1), C(═NR^(e))R^(b1), C(═NR^(e))NR^(c1)R^(d1),NR^(c1)C(═NR^(e))NR^(c1)R^(d1), NHOR^(a1), NR^(c1)S(═O)R^(b1),NR^(c1)S(═O)NR^(c1)R^(d1), S(═O)R^(b1), S(═O)NR^(c1)R^(d1),NR^(c1)S(═O)₂R^(b1), NR^(c1)S(═O)₂NR^(c1)R^(d1), S(═O)₂R^(b1),S(═O)(═NR^(f))R^(b1), and S(═O)₂NR^(c1)R^(d1), wherein said C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(2B) substituents; each R^(a1), R^(c1), and R^(d1) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl,4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with1, 2, 3, or 4 independently selected R^(2B) substituents; each R^(b1) isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 memberedheteroaryl-C₁₋₄ alkyl, each of which are optionally substituted with 1,2, 3, or 4 independently selected R^(2B) substituents; each R^(3A) isindependently selected from H, D, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl,4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄ alkyl,OR^(a2), SR^(a2), C(═O)R^(b2), C(═O)NR^(c2)R^(d2), C(═O)OR^(a2),OC(═O)R^(b2), OC(═O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(═O)R^(b2),NR^(c2)C(═O)OR^(b2) NR^(c2)C(═O)NR^(c2)R^(d2), C(═NR^(e))R^(b2),C(═NR^(e))NR^(c2)R^(d2), NR^(c2)C(═NR^(e))NR^(c2)R^(d2), NHOR^(a2),NR^(c2)S(═O)R^(b2), NR^(c2)S(═O)NR^(c2)R^(d2), S(═O)R^(b2),S(═O)NR^(c2)R^(d2), NR^(c2)S(═O)₂R^(b2), NR^(c2)S(═O)₂NR^(c2)R^(d2),S(═O)₂R^(b2), S(═O)(═NR^(f))R^(b2), and S(═O)₂NR^(c2)R^(d2), whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, C₆-10 aryl, 4-10 membered heterocycloalkyl, 5-10 memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10membered heterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄alkyl are each optionally substituted with 1, 2, 3, or 4 independentlyselected R^(3B) substituents; each R^(a2), R^(c2), and R^(d2) isindependently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 membered heterocycloalkyl-C₁₋₄ alkyl, and5-10 membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, C₆-10 aryl,4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl areeach optionally substituted with 1, 2, 3, or 4 independently selectedR^(3B) substituents; each R^(b2) is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,C₆₋₁₀ aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 4-10 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-10 membered heteroaryl-C₁₋₄ alkyl,each of which are optionally substituted with 1, 2, 3, or 4independently selected R^(3B) substituents; each R^(2B) and R^(3B) isindependently selected from H, D, halo, CN, NO₂, C₃₋₇ cycloalkyl,phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, 5-6 membered heteroaryl-C₁₋₄ alkyl,OR^(a23), SR^(a23), C(═O)R^(b23), C(═O)NR^(c23)R^(d23), C(═O)OR^(a23),OC(═O)R^(b23), OC(═O)NR^(c23)R^(d23), NR^(c23)R^(d23),NR^(c23)C(═O)R^(b23), NR^(c23)C(═O)OR^(b23),NR^(c23)C(═O)NR^(c23)R^(d23), C(═NR^(e))R^(b23),C(═NR^(e))NR^(c23)R^(d23), NR^(c23)C(═NR^(e))NR^(c23)R^(d23),NHOR^(a23), NR^(c23) S(═O)R^(b23), NR^(c23) S(═O)NR^(c23)R^(d23),S(═O)R^(b23), S(═O)NR^(c23)R^(d23), NR^(c23) S(═O)₂R^(b23), NR^(c23)S(═O)₂NR^(c23)R^(d23), S(═O)₂R^(b23), S(═O)(═NR^(f))R^(b23), andS(═O)₂NR^(c23)R^(d23), wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with 1,2, 3, or 4 independently selected R^(G) substituents; each R^(a23),R^(c23), and R^(d23) is independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl, wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl are each optionally substituted with1, 2, 3, or 4 independently selected R^(G) substituents; each R^(b23) isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄alkyl, each of which are optionally substituted with 1, 2, 3, or 4independently selected R^(G) substituents; and each R^(G) isindependently selected from OH, NO₂, CN, halo, C₁₋₃ alkyl, C₂₋₃ alkenyl,C₂₋₃ alkynyl, C₁₋₃ haloalkyl, cyano-C₁₋₃ alkyl, HO—C₁₋₃ alkyl, C₁₋₃alkoxy-C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, amino, C₁₋₃ alkylamino,di(C₁₋₃ alkyl)amino, thio, C₁₋₃ alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃alkylsulfonyl, carbamyl, C₁₋₃ alkylcarbamyl, di(C₁₋₃ alkyl)carbamyl,carboxy, C₁₋₃ alkylcarbonyl, C₁₋₃ alkoxycarbonyl, C₁₋₃ alkylcarbonyloxy,C₁₋₃ alkylcarbonylamino, C₁₋₃ alkoxycarbonylamino, C₁₋₃alkylaminocarbonyloxy, C₁₋₃ alkylsulfonylamino, aminosulfonyl, C₁₋₃alkylaminosulfonyl, di(C₁₋₃ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₃ alkylaminosulfonylamino, di(C₁₋₃ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₃ alkylaminocarbonylamino, and di(C₁₋₃alkyl)aminocarbonylamino.
 2. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R¹ is H.
 3. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R² is selected from C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, each of which is optionally substitutedwith 1, 2, 3, or 4 independently selected R^(2A) substituents.
 4. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R² is selected from 4-7 membered heterocycloalkyl and phenyl,each of which is optionally substituted with 1, 2, 3, or 4 independentlyselected R^(2A) substituents.
 5. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R² is selected frompiperidin-4-yl and phenyl, each of which is substituted with 1 R^(2A)substituent.
 6. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein each R^(2A) is independently selectedfrom halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, OR^(a1), SR^(a1), C(═O)R^(b1), C(═O)NR^(c1)R^(d1),C(═O)OR^(a1), OC(═O)R^(b1), OC(═O)NR^(c1)R^(d1), NR^(c1)R^(d1),NR^(c1)C(═O)R^(b1), NR^(c1)C(═O)OR^(b1), NR^(c1)C(═O)NR^(c1)R^(d1),NHOR^(a1), NR^(c1)S(═O)₂R^(b1), NR^(c1)S(═O)₂NR^(c1)R^(d1),S(═O)₂R^(b1), and S(═O)₂NR^(c1)R^(d1); each R^(a1), R^(c1), and R^(d1)is independently selected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl; andeach R^(b1) is independently selected from C₁₋₆ alkyl and C₁₋₆haloalkyl.
 7. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein at least one R^(2A) is selected from S(═O)₂R^(b1)and S(═O)₂NR^(c1)R^(d1), wherein R^(b1) is C₁₋₃ alkyl; and R^(c1) andR^(d1) are each independently selected from H and C₁₋₃ alkyl.
 8. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein each R^(2A) is independently selected from S(═O)₂CH₃ andS(═O)₂NH₂.
 9. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein R³ is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, each of which is optionally substitutedwith 1, 2, 3, or 4 independently selected R^(3A) substituents.
 10. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R³ is selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl, eachof which is optionally substituted with 1 or 2 independently selectedR^(3A) substituents.
 11. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R³ optionally substituted with 1, 2, 3,or 4 independently selected R^(3A) substituents is selected from1,1-difluorobutan-2-yl, cyclopentyl, phenyl, tetrahydrofuran-3-yl, and(1-methyl-1H-pyrazol-5-yl)methyl.
 12. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein each R^(3A) isindependently selected from halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a2), SR^(a2), C(═O)R^(b2),C(═O)NR^(c2)R^(d2), C(═O)OR^(a2), OC(═O)R^(b2), OC(═O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(═O)R^(b2), NR^(c2)C(═O)OR^(b2),NR^(c2)C(═O)NR^(c2)R^(d2), NHOR^(a2), NR^(c2)S(═O)₂R^(b2),NR^(c2)S(═O)₂NR^(c2)R^(d2), S(═O)₂R^(b2), and S(═O)₂NR^(c2)R^(d2); eachR^(a2), R^(c2), and R^(d2) is independently selected from H, C₁₋₆ alkyl,and C₁₋₆ haloalkyl; and each R^(b2) is independently selected from C₁₋₆alkyl and C₁₋₆ haloalkyl.
 13. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein each R^(3A) isindependently selected from H, halo, C₁₋₆ alkyl, and C₁₋₆ haloalkyl. 14.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R⁴ and R⁵ are each independently selected from C₁₋₆ alkyl andC₁₋₆ haloalkyl; or, alternatively, R⁴ and R⁵, together with the carbonatom to which they are attached form a 3, 4, 5, or 6 membered cycloalkylring.
 15. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R⁴ and R⁵ are each independently C₁₋₆ alkyl.
 16. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R⁴ and R⁵ are each methyl.
 17. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R⁴ and R⁵ are eachmethyl; or R⁴ and R⁵, together with the carbon atom to which they areattached, form a cyclopropyl ring.
 18. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R⁶ and R⁷ are eachindependently selected from H, C₁₋₆ alkyl and C₁₋₆ haloalkyl.
 19. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R⁶ and R⁷ are each H.
 20. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein: R¹ is H; R² isselected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C₃₋₇ cycloalkyl-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, 4-7 memberedheterocycloalkyl-C₁₋₄ alkyl, and 5-6 membered heteroaryl-C₁₋₄ alkyl,each of which is optionally substituted with 1, 2, 3, or 4 independentlyselected R^(2A) substituents; R³ is selected from C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl, 4-7membered heterocycloalkyl, 5-6 membered heteroaryl, C₃₋₇ cycloalkyl-C₁₋₄alkyl, phenyl-C₁₋₄ alkyl, 4-7 membered heterocycloalkyl-C₁₋₄ alkyl, and5-6 membered heteroaryl-C₁₋₄ alkyl, each of which is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(3A)substituents; R⁴ and R⁵ are each independently selected from C₁₋₆ alkyland C₁₋₆ haloalkyl; or, alternatively, R⁴ and R⁵, together with thecarbon atom to which they are attached form a 3, 4, 5, or 6 memberedcycloalkyl ring; R⁶ and R⁷ are each independently selected from H andC₁₋₆ alkyl; each R^(2A) is independently selected from halo, CN, NO₂,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a1),SR^(a1), C(═O)R^(b1), C(═O)NR^(c1)R^(d1), C(═O)OR^(a1), OC(═O)R^(b1),OC(═O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(═O)R^(b1),NR^(c1)C(═O)OR^(b1), NR^(c1)C(═O)NR^(c1)R^(d1), NHOR^(a1),NR^(c1)S(═O)₂R^(b1), NR^(c1)S(═O)₂NR^(c1)R^(d1), S(═O)₂R^(b1), andS(═O)₂NR^(c1)R^(d1); each R^(a1), R^(c1), and R^(d1) is independentlyselected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl; each R^(b1) isindependently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl; each R^(3A)is independently selected from halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, OR^(a2), SR^(a2), C(═O)R^(b2),C(═O)NR^(c2)R^(d2), C(═O)OR^(a2), OC(═O)R^(b2), OC(═O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(═O)R^(b2), NR^(c2)C(═O)OR^(b2),NR^(c2)C(═O)NR^(c2)R^(d2), NHOR^(a2), NR^(c2)S(═O)₂R^(b2),NR^(c2)S(═O)₂NR^(c2)R^(d2), S(═O)₂R^(b2), and S(═O)₂NR^(c2)R^(d2); eachR^(a2), R^(c2), and R^(d2), is independently selected from H, C₁₋₆alkyl, and C₁₋₆ haloalkyl; and each R^(b2) is independently selectedfrom C₁₋₆ alkyl and C₁₋₆ haloalkyl.
 21. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein: R¹ is H; R² isselected from 4-7 membered heterocycloalkyl and phenyl, each of whichare substituted by 1 R^(2A) group; R^(2A) is S(═O)₂R^(b1) orS(═O)₂NR^(c1)R^(d1); R^(b1) is C₁₋₃ alkyl; R^(c1) and R^(d1) are eachindependently selected from H and C₁₋₃ alkyl; R³ is selected from C₁₋₆alkyl, C₃₋₇ cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6membered heteroaryl-C₁₋₄ alkyl, each of which is optionally substitutedwith 1, 2, 3, or 4 independently selected R^(3A) substituents; eachR^(3A) is independently selected from H, halo, C₁₋₆ alkyl, and C₁₋₆haloalkyl; R⁴ and R⁵ are each methyl; or R⁴ and R⁵, together with thecarbon atom to which they are attached form, form a cyclopropyl ring;and R⁶ and R⁷ are each H.
 22. The compound of claim 1, selected from:4-((8-cyclopentyl-6,6-dimethyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-yl)amino)benzenesulfonamide;8-cyclopentyl-6,6-dimethyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one;and6,6-dimethyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)-8-phenyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one;or a pharmaceutically acceptable salt thereof.
 23. The compound of claim1, selected from:8-(1,1-difluorobutan-2-yl)-6,6-dimethyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one;6,6-dimethyl-8-((1-methyl-1H-pyrazol-5-yl)methyl)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one;and6,6-dimethyl-2-((1-(methylsulfonyl)piperidin-4-yl)amino)-8-(tetrahydrofuran-3-yl)-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one;or a pharmaceutically acceptable salt thereof.
 24. A pharmaceuticalcomposition comprising a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier. 25.A method of inhibiting CDK2, comprising contacting the CDK2 with acompound of claim
 1. 26. A method of inhibiting CDK2 in a patient,comprising administering to the patient a compound of claim 1, or apharmaceutically acceptable salt thereof.
 27. A method of treating adisease or disorder associated with CDK2 in a patient, comprisingadministering to the patient a therapeutically effective amount of acompound of claim 1, or a pharmaceutically acceptable salt thereof. 28.The method of claim 27, wherein the disease or disorder is cancer.